Machine Learning Discoveries of BLM-X Synergy in ETC-1922159 Treated Colorectal Cancer Cells

Machine learning discoveries of BLM-X synergy in ETC-1922159 treated colorectal cancer cells shriprakash sinha Independent Researcher; Orcid ID : orcid.org/0000-0001-7027-5788 104-Madhurisha Heights Phase 1, Risali, Bhilai-490006, India Abstract Bloom syndrome/BLM RecQ like helicase (BLM) is a gene, mutations in which causes a rare autosomal recessive genetic disorder called Bloom syndrome. This is characterized by predisposition to the development of cancer, short stature, and genomic instability. RecQ like helicase is a family of helicase enzymes or motor proteins that drive the unwinding of paired DNA by moving directionally along a nucleotidic backbone in the 3’ to 5’ direction, thus separating two hybridized nucleic acid strands using energy from ATP hydrolysis. In colorectal cancer (CRC) cells treated with ETC1922159, BLM was found to be down regulated along with other genes. A recently developed search engine ranked combinations of BLM-X (X, a particular gene/protein) at 2nd order level after drug administration. Some of these combinations have been tested in wet lab, however many have been pointed out by the search engine that are yet to be explored/tested. These rankings reveal which BLM-X combinations might be working synergistically in CRC. In this research work, I cover combinations of BLM with members of BRCA DNA repair associated (BRCA), DNA topoisomerase (TOP), RecQ mediated genome instability (RMI), DNA replication helicase/nuclease 2 (DNA2), budding uninhibited by benzimidazoles mitotic checkpoint serine/threonine kinase (BUB), cyclin dependent kinase (CDK), polo like kinase (PLK), Fanconi anemia complementation group (FANC), heterogeneous nuclear ribonucleoprotein (HNRNP), minichromosome maintenance complex component (MCM), poly(ADP-ribose) polymerase (PARP), DNA polymerase (POL), DNA-dependent RNA polymerase (POLR), ubiquitin specific peptidase (USP) and structural maintenance of chromosomes (SMC) family. Keywords: BLM, Porcupine inhibitor ETC-1922159, Sensitivity analysis, Machine learning, Colorectal cancer. ✩ML dicoveries of BLM-X synergy in ETC-1922159 treated CRC cells Email address: [email protected] (shriprakash sinha) 1Aspects of unpublished work were presented in a poster session at the first Wnt Gordon Research Conference, from 6-11 August 2017, held in Stowe, VT 05672, USA. Preprint submitted to Preprint December 15, 2025 1. Introduction 1.1. BLM BLM encodes a protein containing seven motifs which are conserved in DNA and RNA helicases. Karow et al. [1] show that the ATPase activity of recombinant BLM protein is stimulated by either singleor doublestranded DNA and BLM exhibits ATPand Mg2+- dependent DNA helicase activity that displays 3’-5’ directionality. The crystal structure of BLM, as investigated by Newman et al. [2] show a nucleotide-dependent interaction of the core helicase domain with the conserved helicase and RNase D Cterminal (HRDC) domain. BLM known to unwind DNA secondary structures such as G-quadruplexes (G4s) and Danino et al. [3] demonstrate that BLM is recruited to stress granules (SGs) and is enriched in SGs upon different stress conditions and in an RNA G-quadruplexes (rG4)- dependent manner. Further, they show that BLM unwinds rG4s (as it unwinds DNA secondary structure G4) and acts as a negative regulator of SG formation. BLM is a genome stabilizer involved in the regulation of DNA replication and recombination. Mutations in the BLM gene cause genomic instability, premature aging, predisposition to cancer, immunodeficiency, and pulmonary diseases. These point to BLM being a tumor suppressor. However, Kaur et al. [4] also suggest that BLM is a proto-oncogene as it undergoes various types of alterations including increase in the transcript, copy number, and protein levels in multiple types of cancers. In multiple myeloma (MM) cells, Ovejero et al. [5] show that treatment with melphalan produced DNA damage. MM cells where BLM was overexpressed, could cope with the drug-induced DNA damage and survive the treatment, thus showing resistance. However, BLM inhibition in combination with melphalan increased DNA damage in such a way that these cells could not efficiently repair, thus leading to cell cycle arrest and cell death, and further overcame melphalan resistance. In colorectal cancer (CRC) cells treated with ETC-1922159, BLM was found to be down regulated along with other genes. Some combinations of BLM have been confirmed in wet lab, however, many of the combinations have not been explored/tested or are known. To reveal these combinations, I use a modification of a recently published machine learning based search engine, details of which are given in the next section. 1.2. Combinatorial search problem and a possible solution In a recently published work Sinha [6], a frame work of a search engine was developed which can rank combinations of factors (genes/proteins) in a signaling pathway. Readers are requested to go through the adaptation of the above mentioned work for gaining deeper insight into the working of the pipeline and its use of published data set generated after administration of ETC-1922159, Sinha [7]. The work uses SVM package by Joachims [8] in https://www.cs.cornell.edu/people/tj/svm_light/svm_ rank.html. I use the adaptation to rank 2nd order gene combinations. 2 2. Results & Discussion 2.1. BLM related synergies 2.1.1. BLM - BRCA Tsukada et al. [9] show that BLM and BRCA1-BARD1 coordinate mechanisms of joint DNA molecule resolution and combined deficiency in BLM and BRCA1-BARD1 (but not BRCA2) is synthetically lethal. They identify a negative genetic interaction between BLM loss and deficiency in the BRCA1-BARD1 tumor suppressor complex. Consequently, cells with defective BLM and BRCA1-BARD1 accumulate catastrophic levels of chromosome breakage and micronucleation, leading to cell death. Finally, Wu et al. [10] have demonstrated that BRCA1 forms a heterodimeric complex with BARD1, and both proteins depend on each other for mutual stability. In colorectal cancer cells treated with ETC-1922159, BRCA family members, BARD1, and BLM, were found to be down regulated and their regulation was recorded independently. I was able to rank 2nd order combination of these BRCA members and BARD1 along with BLM. Table 1 shows rankings of these combinations. Followed by this is the unexplored combinatorial hypotheses in table 2 generated from analysis of the ranks in table 1. The table 1 shows rankings of BRCA members/BARD1 w.r.t BLM. BRCA1 - BLM shows low ranking of 289 (linear) and 376 (rbf). BRCA2 - BLM shows low ranking of 344 (linear) and 484 (rbf). BARD1 - BLM shows low ranking of 1085 (laplace) and 1136 (linear). These rankings point to the synergy existing between the two components, which have been down regulated after the drug treatment. Important to note is that BRCA2 also showed synergy with BLM in colorectal cancer, as its combination was assigned a low valued rank for ETC-1922159 treated colorectal cancer. RANKING BRCA FAMILY/BARD1 VS BLM RANKING OF BRCA FAMILY/BARD1 W.R.TBLM laplace linear rbf BRCA1 - BLM 1807 289 376 BRCA2 - BLM 1770 344 484 BARD1 - BLM 1085 1136 1801 Table 1: 2nd order interaction ranking between BLM VS BRCA members/BARD1. One can also interpret the results of the table 1 graphically, with the following influences - •BRCA members w.r.t BLM with BLM −>BRCA-1/2 and •BARD1 w.r.t BLM with BLM −>BARD1. 3 UNEXPLORED COMBINATORIAL HYPOTHESES BRCA members/BARD1 w.r.t BLM BRCA-1/2 BLM BARD1 BLM Table 2: 2nd order combinatorial hypotheses between BLM and BRCA members. 2.1.2. BLM - TOP/RMI DNA resection is a process in which the nucleolytic processing of broken DNA ends happen as a first step of homologous recombination. This resection is orchestrated by a multienzyme complex that comprises of BLM, DNA2 and additional DNA-binding proteins. Using single-molecule imaging, Soniat et al. [11] show that BLM partners with TOP3A-RMI1/2 to form the BLM-TOP3A-RMI1/2 (BTRR) complex and determined that TOP3A-RMI1/2 aids BLM in initiating DNA unwinding, and along with MRE11-RAD50-NBS1 (MRN) complex, stimulates DNA2-mediated resection. Thus a synergy exists among these factors. In colorectal cancer cells treated with ETC1922159, TOP/RMI family members, DNA2, and BLM, were found to be down regulated and their regulation was recorded independently. I was able to rank 2nd order combination of these TOP/RMI members and DNA2 along with BLM. Table 3 shows rankings of these combinations. Followed by this is the unexplored combinatorial hypotheses in table 4 generated from analysis of the ranks in table 3. The table 3 shows rankings of TOP-RMI members/BARD1 w.r.t BLM. TOP2A - BLM shows low ranking of 206 (linear) and 366 (rbf). RMI1 - BLM shows low ranking of 133 (laplace) and 994 (linear). RMI2 - BLM shows low ranking of 185 (linear) and 12 (rbf). DNA2 - BLM shows low ranking of 596 (linear) and 566 (rbf). These rankings point to the synergy existing between the two components, which have been down regulated after the drug treatment. Note that RMI-1/2 and DNA2 appear to show synergy in line with what has been established in the reference above. TOP2A was the only member of TOP family which showed synergy with BLM. The data do not contain recordings of TOP3A. Further, TOP2B, TOPBP1 and TOP1MT showed high ranking and might not be synergistically working with BLM, before treatment. One can also interpret the results of the table 3 graphically, with the following influences - •TOP-RMI members w.r.t BLM with BLM −>TOP2A and BLM −> RMI-1/2 and •DNA2 w.r.t BLM with BLM −>DNA2. 2.1.3. BLM - BUB Telomeres and telomere-binding proteins form nucleoprotein structures to maintain genome integrity but can present serious challenges during telomere DNA replication. Li et al. [12] show that the BUB3-BUB1 complex, a component in SAC, binds to telom4 RANKING TOP-RMI FAMILY/DNA2 VS BLM RANKING OF TOP-RMI FAMILY/DNA2 W.R.TBLM laplace linear rbf TOP2B - BLM 829 1582 1735 TOPBP1 - BLM 1658 1638 2351 TOP2A - BLM 1659 206 366 TOP1MT - BLM 2513 2414 934 RMI1 - BLM 133 994 1582 RMI2 - BLM 1977 185 12 DNA2 - BLM 2396 596 566 Table 3: 2nd order interaction ranking between BLM VS TOP-RMI members/BARD1. UNEXPLORED COMBINATORIAL HYPOTHESES TOP-RMI members/DNA2 w.r.t BLM TOP2A BLM RMI-1/2 BLM DNA2 BLM Table 4: 2nd order combinatorial hypotheses between BLM and TOP-RMI members. eres during S phase and promotes telomere DNA replication, and demonstrate that the telomere-binding ability of BUB3 and kinase activity of BUB1, are indispensable to BUB3-BUB1 function at telomeres. They observe that TRF2 targets BUB1-BUB3 to telomeres, and BUB1 directly phosphorylates TRF1 and promotes TRF1 recruitment of BLM helicase to overcome replication stress. Thus there exists a synergy between BUB family and BLM. In colorectal cancer cells treated with ETC-1922159, BUB family members, and BLM, were found to be down regulated and their regulation was recorded independently. I was able to rank 2nd order combination of these BUB members along with BLM. Table 5 shows rankings of these combinations. Followed by this is the unexplored combinatorial hypotheses in table 6 generated from analysis of the ranks in table 5. The table 5 shows rankings of BUB members w.r.t BLM. BUB3 - BLM shows low ranking of 1070 (laplace) and 731 (rbf). BUB1B - BLM shows low ranking of 67 (linear) and 469 (rbf). BUB1 - BLM shows low ranking of 156 (linear) and 412 (rbf). These rankings point to the synergy existing between the two components, which have been 5 down regulated after the drug treatment. Note that BUB-1/3 appear to show synergy in line with what has been established in the reference above. Apart form that BUB1B also shows synergy. RANKING BUB FAMILY VS BLM RANKING OF BUB FAMILY W.R.TBLM laplace linear rbf BUB3 - BLM 1070 2180 731 BUB1B - BLM 1894 67 469 BUB1 - BLM 2718 156 412 Table 5: 2nd order interaction ranking between BLM VS BUB members/BARD1. One can also interpret the results of the table 5 graphically, with the following influences - •BUB members w.r.t BLM with BLM −>BUB-3/1/1B. UNEXPLORED COMBINATORIAL HYPOTHESES BUB members w.r.t BLM BUB-3/1/1B BLM Table 6: 2nd order combinatorial hypotheses between BLM and BUB members. 2.1.4. BLM - CDK/PLK As seen earlier, BLM helicase functions with TOP3A and RMI-1/2 (BTR complex) to dissolve recombination intermediates and avoid somatic crossing-over. Balbo Pogliano et al. [13] show that crossover avoidance by BTR requires the activity of cyclin-dependent kinase-1 (CDK1), Polo-like kinase-1 (PLK1), and the DDR mediator protein TOPBP1. They observe that CDK1 phosphorylates BLM and TOPBP1 and promotes the interaction of both proteins with PLK1. This stimulates the dissolution of topologically linked DNA intermediates by BLM-TOP3A. However, in our about analysis we found that the engine did not rank the combination of TOPBP1-BLM appropriately, as it showed higher ranks maening no synergistic affect in colorectal cancer before the treatment with ETC-1922159. Nevertheless, in colorectal cancer cells treated with ETC1922159, CDK-PLK family members and BLM, were found to be down regulated and their regulation was recorded independently. I was able to rank 2nd order combination of these CDK-PLK members along with BLM. 6 Table 7 shows rankings of these combinations. Followed by this is the unexplored combinatorial hypotheses in table 8 generated from analysis of the ranks in table 7. The table 7 shows rankings of CDK-PLK members w.r.t BLM. CDK20 - BLM shows low ranking of 854 (laplace), 1168 (linear) and 906 (rbf). CDK1 - BLM shows low ranking of 223 (linear) and 327 (rbf). PLK1 - BLM shows low ranking of 507 (linear) and 532 (rbf). PLK4 - BLM shows low ranking of 23 (linear) and 189 (rbf). These rankings point to the synergy existing between the two components, which have been down regulated after the drug treatment. Further, CDK4 and CDK6 showed high ranking with BLM, thus indicating that they might not be working synergistically with BLM, before the drug treatment. RANKING CDK-PLK FAMILY VS BLM RANKING OF CDK-PLK FAMILY W.R.TBLM laplace linear rbf CDK20 - BLM 854 1168 906 CDK4 - BLM 1840 1457 1577 CDK6 - BLM 1858 1315 1707 CDK1 - BLM 2375 223 327 PLK1 - BLM 1753 507 532 PLK4 - BLM 2394 23 189 Table 7: 2nd order interaction ranking between BLM VS CDK-PLK members. One can also interpret the results of the table 7 graphically, with the following influences - •CDK members w.r.t BLM with BLM −>CDK-20/1 and •PLK members w.r.t BLM with BLM −>PLK-1/4. UNEXPLORED COMBINATORIAL HYPOTHESES CDK members w.r.t BLM CDK-20/1 BLM PLK members w.r.t BLM PLK-1/4 BLM Table 8: 2nd order combinatorial hypotheses between BLM and CDK-PLK members. 7 2.1.5. BLM - FANC Fanconi anaemia (FA) and Bloom syndrome are autosomal recessive diseases characterised by chromosome fragility and cancer proneness. Pichierri et al. [14] provide evidence that BLM and FANCD2 colocalise and coimmunoprecipitate in response to crosslinked DNA and stalled replication forks. They also found that the FA core complex phosphorylated BLM and its assembly in nuclear foci in response to crosslinked DNA. Lansdorp and van Wietmarschen [15] in their review indicate that FANCJ maintains epigenetic stability in tandem with the BLM helicase and acts on Guanine quadruplex (G4) DNA structures. The collapse of stalled replication forks drives genomic instability. Several mechanisms exist to resolve the subsequent replication stress. Cancer cells that use Alternative Lengthening of Telomeres (ALT) show higher levels of telomere-specific replication stress, and co-opt stalled replication forks as substrates for break-induced telomere synthesis. FANCM forms independent interactions with the BLM-TOP3A-RMI (BTR) complex and the FA core complex. Lu et al. [16] demonstrate that FANCM depletion incites ALT activity and FANCM-mediated attenuation of ALT demands its inherent DNA translocase activity and interaction with the BTR complex, but does not require the FA core complex. In colorectal cancer cells treated with ETC-1922159, FANC family members and BLM, were found to be down regulated and their regulation was recorded independently. I was able to rank 2nd order combination of these FANC members along with BLM. Table 9 shows rankings of these combinations. Followed by this is the unexplored combinatorial hypotheses in table 10 generated from analysis of the ranks in table 9. The table 9 shows rankings of FANC members w.r.t BLM. FANCB - BLM shows low ranking of 957 (laplace), 246 (linear) and 261 (rbf). FANCI - BLM shows low ranking of 1081 (linear) and 1472 (rbf). FANCM - BLM shows low ranking of 535 (linear) and 668 (rbf). FANCD2 - BLM shows low ranking of 38 (linear) and 78 (rbf). These rankings point to the synergy existing between the two components, which have been down regulated after the drug treatment. Further, FANCG, FANCF and FANCD2OS showed high ranking with BLM, thus indicating that they might not be working synergistically with BLM, before the drug treatment. One can also interpret the results of the table 9 graphically, with the following influences - •FANC members w.r.t BLM with BLM −>FANC-B/I/M/D2. 2.1.6. BLM - HNRNP DNA double-strand break (DSB) signaling and repair are crucial for cell viability. Polo et al. [17] show that HNRNPUL-1/2 play important roles in cellular responses to DSBs as they act as binding partners for the DSB sensor complex MRE11-RAD50-NBS1 (MRN). Further, they establish that HNRNPUL-1/2 function downstream of MRN and CtBP-interacting protein (CtIP) to promote recruitment of the BLM helicase to DNA breaks. In colorectal cancer cells treated with ETC-1922159, HNRNP family members and BLM, were found to be down regulated and their regulation was recorded independently. I was able to rank 2nd order combination of these HNRNP members along with BLM. 8 RANKING FANC FAMILY VS BLM RANKING OF FANC FAMILY W.R.TBLM laplace linear rbf FANCD2OS - BLM 336 2152 1965 FANCB - BLM 957 246 261 FANCI - BLM 1825 1081 1472 FANCM - BLM 1943 535 668 FANCG - BLM 2438 2718 607 FANCF - BLM 2478 2031 2544 FANCD2 - BLM 2716 38 78 Table 9: 2nd order interaction ranking between BLM VS FANC members. UNEXPLORED COMBINATORIAL HYPOTHESES FANC members w.r.t BLM FANC-B/I/M/D2 BLM Table 10: 2nd order combinatorial hypotheses between BLM and FANC members. Table 11 shows rankings of these combinations. Followed by this is the unexplored combinatorial hypotheses in table 12 generated from analysis of the ranks in table 11. The table 11 shows rankings of HNRNP members w.r.t BLM. HNRNPC - BLM shows low ranking of 379 (laplace) and 1269 (linear). HNRNPR - BLM shows low ranking of 391 (laplace) and 1349 (linear). HNRNPA0 - BLM shows low ranking of 1141 (laplace) and 1353 (linear). HNRNPA1L2 - BLM shows low ranking of 1255 (laplace) and 982 (rbf). These rankings point to the synergy existing between the two components, which have been down regulated after the drug treatment. Further, HNRNPA3, HNRNPD, HNRNPM, HNRNPH3 and HNRNPA1 showed high ranking with BLM, thus indicating that they might not be working synergistically with BLM, before the drug treatment. One can also interpret the results of the table 11 graphically, with the following influences - •HNRNP members w.r.t BLM with BLM −>HNRNP-C/R/A0/A1L2. 9 2.1.11. BLM - SMC During Caenorhabditis elegans meiosis recombionation, Hong et al. [22] show that the SMC-5/6 complex acts synergistically with HIM-6 (an ortholog of the human BLM). This concerted action of the SMC-5/6 complex and HIM-6/BLM is important for processing recombination intermediates, crossover regulation and bivalent maturation. In colorectal cancer cells treated with ETC-1922159, SMC family members and BLM, were found to be down regulated and their regulation was recorded independently. I was able to rank 2nd order combination of these SMC members along with BLM. Table 21 shows rankings of these combinations. Followed by this is the unexplored combinatorial hypotheses in table 22 generated from analysis of the ranks in table 21. The table 21 shows rankings of SMC members w.r.t BLM. SMC4 - BLM shows low ranking of 754 (laplace), 684 (linear) and 1210 (rbf). SMC1A - BLM shows low ranking of 1528 (laplace) and 1042 (rbf). SMC2 - BLM shows low ranking of 725 (linear) and 696 (rbf). These rankings point to the synergy existing between the two components, which have been down regulated after the drug treatment. RANKING SMC FAMILY VS BLM RANKING OF SMC FAMILY W.R.TBLM laplace linear rbf SMC4 - BLM 754 684 1210 SMC1A - BLM 1528 2133 1042 SMC2 - BLM 2123 725 696 Table 21: 2nd order interaction ranking between BLM VS SMC members. One can also interpret the results of the table 21 graphically, with the following influences - •SMC members w.r.t BLM with BLM −>SMC-4/1A/2. UNEXPLORED COMBINATORIAL HYPOTHESES SMC members w.r.t BLM SMC-4/1A/2 BLM Table 22: 2nd order combinatorial hypotheses between BLM and SMC members. 16 3. Conclusion Presented here are a range of multiple synergistic BLM 2nd order combinations that were ranked via a machine learning based search engine. Via majority voting across the ranking methods, it was possible to find plausible unexplored synergistic combinations of BLM-X that might be prevalent in CRC cells after treatment with ETC-1922159 drug. Conflict of interest There are no conflicts to declare. Author’s contributions Concept, design, in silico implementation - SS. Analysis and interpretation of results - SS. Manuscript writing - SS. Manuscript revision - SS. Approval of manuscript - SS Acknowledgements Special thanks to Mrs. Rita Sinha and late Mr. Prabhat Sinha for supporting the author financially, without which this work could not have been made possible. Source of Data Data used in this research work was released in a publication in Madan et al. [23]. 4. References References [1] J. K. Karow, R. K. Chakraverty, I. D. Hickson, The bloom’s syndrome gene product is a 3’-5’ dna helicase, Journal of Biological Chemistry 272 (1997) 30611–30614. [2] J. A. Newman, P. Savitsky, C. K. Allerston, A. H. Bizard, ¨ O. ¨ Ozer, K. 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