The role of Double Strand Break Repair, Translesion Synthesis and Interstrand Crosslinks in Colorectal Cancer progression – clinicopathological data and survival.

Laporte, Gustavo Andreazza; Leguisamo, Natalia Motta; Glória, Helena; Azambuja, Daniel de Barcellos; Kalil, Antônio Nocchi; Saffi, Jenifer

doi:10.21203/rs.2.10554/v1

Cited by 2 publications

(2 citation statements)

References 42 publications

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“…2016; Wang et al . 2016; Laporte et al . 2020); therefore, elucidation of the mechanism underlying the subcellular distribution of SNM1A would help in better understanding of its function in caner susceptibility.…”

Section: Discussionmentioning

confidence: 99%

Dual targeting ofSaccharomyces cerevisiaePso2 to mitochondria and the nucleus, and its functional relevance in the repair of DNA interstrand crosslinks

Muniyappa

Somashekara

2022

Preprint

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Repair of DNA interstrand crosslinks (ICLs) involves a functional interplay among different DNA surveillance and repair pathways. Previous work has shown that ICL-inducing agents cause damage to Saccharomyces cerevisiae nuclear and mitochondrial DNA (mtDNA), and its pso2/snm1 mutants exhibit a petite phenotype followed by loss of mtDNA integrity and copy number. Complex as it is, the cause and underlying molecular mechanisms remains elusive. Here, by combining a wide range of approaches with in vitro and in vivo analyses, we assessed the subcellular localization and function of Pso2. We found evidence that the nuclear-encoded Pso2 contains one mitochondrial targeting sequence (MTS) and two nuclear localization signals (NLS1 and NLS2), although NLS1 resides within the MTS. Further analysis revealed that Pso2 is a dual-localized ICL repair protein; it can be imported into both nucleus and mitochondria, and that genotoxic agents enhance its abundance in the latter. While MTS is essential for mitochondrial Pso2 import, either NLS1 or NLS2 is sufficient for its nuclear import; this implies that the two NLS motifs are functionally redundant. Ablation of MTS abrogated mitochondrial Pso2 import, and concomitantly, raised its levels in the nucleus. Strikingly, mutational disruption of both NLS motifs blocked the nuclear Pso2 import; at the same time, they enhanced its translocation into the mitochondria, consistent with the notion that the relationship between MTS and NLS motifs is competitive. However, the nuclease activity of import-deficient species of Pso2 was not impaired. The potential relevance of dual-targeting of Pso2 into two DNA-bearing organelles is discussed.

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Section: Discussionmentioning

confidence: 99%

Dual targeting ofSaccharomyces cerevisiaePso2 to mitochondria and the nucleus, and its functional relevance in the repair of DNA interstrand crosslinks

Muniyappa

Somashekara

2022

Preprint

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“…The gene DCLRE1A has been suggested to have a role in double-strand break repair, translation synthesis, and interstrand crosslinking in CRC progression and survival. 33 The gene NHLRC2 has been shown in a study of CRC carcinogenesis and to lead to apoptotic cell death in the HCT116 human colon cancer cell line. 34 The haplotype on 15q22.31, runs over five different genes (RBPMS.2 PIF1, PLEKHO2, ANKDD1, HIF1α, and SPG21), with the highest OR for the biggest haplotype, covering all five (Figure S4E and Table S4).…”

Section: Discussionmentioning

confidence: 99%

Colorectal cancer risk susceptibility loci in a Swedish population

Liu

Mahdessian

Helgadottir

et al. 2021

Molecular Carcinogenesis

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To search for colorectal cancer (CRC) risk loci, Swedish samples were used for a genome-wide haplotype analysis. A logistic regression model was employed in 2663 CRC cases and 1642 controls in the discovery analysis. Three analyses were done, on all, familial-, and nonfamilial CRC samples and only results with odds ratio (OR) > 1 were analyzed. single nucleotide polymorphism (SNP) analysis did not generate any statistically significant results. Haplotype analysis suggested novel loci, on chromosome 2q36.1 (OR = 1.71, p value = 5.6924 × 10 −8 ) in all CRC samples, chromosome 1q43 (OR = 4.04 p value = 3.24 × 10 −8 ) in familial CRC samples, and two hits in nonfamilial CRC samples, chromosomes 2q36.1 (OR = 1.71 p value = 5.69 × 10 −8 ) and 3p24.3 (OR = 1.62 p value = 6.21 × 10 −9 ). Moreover, one locus on chromosome 20q13.33 was suggested in analyses of all samples, and five more novel loci were suggested on chromosomes 10q25. 3, 15q,22.31, 17p11.2, 1p34.2, and 3q24. The haplotypes from the analysis of all samples were replicated in a second study of CRC cases and controls from the same part of Sweden. In summary, using haplotype analysis in Swedish CRC samples, the best hits were novel loci and the locus on chromosomes 2q36.1 and 20q13.33 suggested in the analysis of all samples were confirmed in a second cohort. The ORs were often higher than ORs from published genome-wide association study (GWAS). The study suggested it was possible that a risk locus could involve more than one gene, and that haplotypes could give information on the gene or genes possibly involved in the risk at specific locus.

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The role of Double Strand Break Repair, Translesion Synthesis and Interstrand Crosslinks in Colorectal Cancer progression – clinicopathological data and survival.

Cited by 2 publications

References 42 publications

Dual targeting ofSaccharomyces cerevisiaePso2 to mitochondria and the nucleus, and its functional relevance in the repair of DNA interstrand crosslinks

Dual targeting ofSaccharomyces cerevisiaePso2 to mitochondria and the nucleus, and its functional relevance in the repair of DNA interstrand crosslinks

Colorectal cancer risk susceptibility loci in a Swedish population

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