scholarly journals Race specific differences in DNA damage repair dysregulation in breast cancer and association with outcome

2020 ◽  
Author(s):  
Aloran Mazumder ◽  
Athena Jimenez ◽  
Rachel E Ellsworth ◽  
Stephen J Freedland ◽  
Sophia George ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Strand Break ◽  
Normal Breast ◽  
Breast Cancer Patients ◽  
Poor Survival ◽  
Single Strand Break ◽  
Multiple Datasets ◽  
Single Strand Break Repair ◽  
Damage Repair ◽  
Break Repair

AbstractIMPORTANCEAfrican American (AA) breast cancer patients have worse outcomes than Caucasian Americans (CAs). DNA damage repair (DDR) genes drive poor outcome in CA estrogen receptor (ER)+ breast cancer patients. Whether DDR genes similarly impact survival in AAs is unknown. Identifying AA-specific patterns of DDR dysregulation could change how we tailor predictive/prognostic biomarkers.OBJECTIVETo characterize DDR dysregulation in ER+ AA patient tumors and test associations with clinical outcome.DESIGN SETTINGS AND PARTICIPANTSThree independent tumor, and two normal breast datasets were analyzed. Tumor datasets: (1) GSE78958 (2) GSE18229 (3) The Cancer Genome Atlas (TCGA). Normal datasets: (4) GSE43973 (5) GSE50939.MAIN OUTCOME AND MEASURESUp/down-regulation of 104 DDR genes was assessed in AA samples vs CAs. Survival associations were assessed for genes dysregulated in multiple datasets.RESULTSOverall, RNA levels of single strand break repair (SSBR) genes were downregulated in AA tumors and double strand break repair (DSBR) genes were upregulated compared to CAs. While SSBR downregulation was mainly detected in tumors, DSBR upregulation was detectable in both tumor and normal breast AA samples. Seven specific DDR genes identified as dysregulated in AAs vs CAs in multiple datasets associated with poor survival. A subset of tumors with simultaneous dysregulation of homologous recombination and single strand break repair genes was enriched in AAs and had associated consistently with poor survival.CONCLUSION AND RELEVANCEOverall, these results constitute the first systematic analysis of differences in DDR regulation in AA ER+ tumors and normal tissue vs CAs. We identify a profile of DDR dysregulation enriched in AA patients, which associates with poor outcome. These results suggest a distinct molecular mechanism of DDR regulation in AAs that lays the groundwork for refining biomarker profiles by race and improving precision medicine for underserved populations.

End-damage-specific proteins facilitate recruitment or stability of X-ray cross-complementing protein 1 at the sites of DNA single-strand break repair

FEBS Journal ◽  
2005 ◽  
Vol 272 (22) ◽  
pp. 5753-5763 ◽  
Author(s):  
Jason L. Parsons ◽  
Irina I. Dianova ◽  
Emma Boswell ◽  
Michael Weinfeld ◽  
Grigory L. Dianov
Keyword(s):  
Strand Break ◽  
Single Strand ◽  
Single Strand Break ◽  
X Ray ◽  
Single Strand Break Repair ◽  
Specific Proteins ◽  
Break Repair

scholarly journals Efficient Single-Strand Break Repair Requires Binding to Both Poly(ADP-Ribose) and DNA by the Central BRCT Domain of XRCC1

Cell Reports ◽  
2019 ◽  
Vol 26 (3) ◽  
pp. 573-581.e5 ◽  
Author(s):  
Luis M. Polo ◽  
Yingqi Xu ◽  
Peter Hornyak ◽  
Fernando Garces ◽  
Zhihong Zeng ◽  
...  
Keyword(s):  
Strand Break ◽  
Single Strand ◽  
Brct Domain ◽  
Single Strand Break ◽  
Single Strand Break Repair ◽  
Break Repair

scholarly journals TDP1 facilitates chromosomal single-strand break repair in neurons and is neuroprotective in vivo

2007 ◽  
Vol 26 (22) ◽  
pp. 4720-4731 ◽  
Author(s):  
Sachin Katyal ◽  
Sherif F El-Khamisy ◽  
Helen R Russell ◽  
Yang Li ◽  
Limei Ju ◽  
...  
Keyword(s):  
Strand Break ◽  
Single Strand ◽  
Single Strand Break ◽  
Single Strand Break Repair ◽  
Break Repair

scholarly journals Pathological mutations in PNKP trigger defects in DNA single-strand break repair but not DNA double-strand break repair

2020 ◽  
Vol 48 (12) ◽  
pp. 6672-6684 ◽  
Author(s):  
Ilona Kalasova ◽  
Richard Hailstone ◽  
Janin Bublitz ◽  
Jovel Bogantes ◽  
Winfried Hofmann ◽  
...  
Keyword(s):  
Strand Break ◽  
Single Strand ◽  
Dna Double Strand Breaks ◽  
Fha Domain ◽  
Single Strand Break ◽  
Strand Breaks ◽  
Charcot Marie Tooth Disease ◽  
Single Strand Break Repair ◽  
Primary Determinant ◽  
Break Repair

Abstract Hereditary mutations in polynucleotide kinase-phosphatase (PNKP) result in a spectrum of neurological pathologies ranging from neurodevelopmental dysfunction in microcephaly with early onset seizures (MCSZ) to neurodegeneration in ataxia oculomotor apraxia-4 (AOA4) and Charcot-Marie-Tooth disease (CMT2B2). Consistent with this, PNKP is implicated in the repair of both DNA single-strand breaks (SSBs) and DNA double-strand breaks (DSBs); lesions that can trigger neurodegeneration and neurodevelopmental dysfunction, respectively. Surprisingly, however, we did not detect a significant defect in DSB repair (DSBR) in primary fibroblasts from PNKP patients spanning the spectrum of PNKP-mutated pathologies. In contrast, the rate of SSB repair (SSBR) is markedly reduced. Moreover, we show that the restoration of SSBR in patient fibroblasts collectively requires both the DNA kinase and DNA phosphatase activities of PNKP, and the fork-head associated (FHA) domain that interacts with the SSBR protein, XRCC1. Notably, however, the two enzymatic activities of PNKP appear to affect different aspects of disease pathology, with reduced DNA phosphatase activity correlating with neurodevelopmental dysfunction and reduced DNA kinase activity correlating with neurodegeneration. In summary, these data implicate reduced rates of SSBR, not DSBR, as the source of both neurodevelopmental and neurodegenerative pathology in PNKP-mutated disease, and the extent and nature of this reduction as the primary determinant of disease severity.

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