[논문]Regulation of DNA repair in the absence of classical non-homologous end joining

Kang, Youn-Jung; Yan, Catherine T.

doi:10.1016/j.dnarep.2018.06.001

Regulation of DNA repair in the absence of classical non-homologous end joining

DNA repair, v.68, 2018년, pp.34 - 40

Kang, Youn-Jung (School of Medicine, Department of Biochemistry, CHA University) , Yan, Catherine T. (Department of Pathology, Beth Israel Deaconess Medical Center)

Abstract ▼ AI-Helper

Abstract Classical non-homologous end-joining (cNHEJ) is the main pathway for the repair of DNA double strand breaks (DSBs) in mammalian cells. In the absence of c-NHEJ, an alternative end-joining (A-EJ) mechanism resolves DSBs. To date, no A-EJ specific factor has been identified. Instead, this mechanism appears to co-opt proteins involved in more than one DNA repair pathway. These include components of base-excision repair (PARP1/XRCC1/LIG3), interstrand cross-link repair (BRCA1/FANCD2), and DSB response/DNA end-resection (MRE11A/RAD50/RBBP8). To clarify the contribution of these factors to A-EJ, here we examined their expression and recruitment to DSBs in correlation with surrogates of cNHEJ (53BP1) and homologous recombination (RAD51) in cells deficient for the cNHEJ end-ligation component XRCC4. This revealed XRCC4-deficient cells exhibited marked increases in the stability of A-EJ transcripts that result in correspondingly elevated levels of associated proteins, in comparison to WT cells. RAD51 was also increased while 53BP1 was unaffected. Treatment with radiomimetic DSB-inducing drug doxorubicin did not influence these activities. However, FANCD2, BRCA1 and XRCC1 foci, prominently associated with 53BP1 foci and hence DSBs resolved by cNHEJ, were only detected in doxorubicin-treated XRCC4-deficient cells. Strikingly, treatment of XRCC4-deficient cells with the PARP-specific inhibitor Niraparib enhanced A-EJ, and substantially induced 53BP1 transcripts and the numbers of A-EJ-associated 53BP1 DNA damage foci. RAD51 was severely inhibited, and upstream cNHEJ (KU70/KU80/DNA-PKCs/ARTEMIS) transcripts were substantially induced. These latter results were recapitulated in BRCA1-deficient cells, which contrastingly did not affect 53BP1 or PARP1 status irrespective of doxorubicin or Niraparib treatment. Hence A-EJ is regulated transcriptionally, reduced by a higher turnover rate in cNHEJ-proficient cells and sustained but fine-tuned by PARP1 in XRCC4-deficient cells to promote DNA repair and survival. Upstream cNHEJ components are similarly transcriptionally down-modulated by PARP1 and BRCA1 in a manner inversely correlated with HR and mechanistically distinct from A-EJ respectively in cNHEJ-deficient and cNHEJ-proficient settings.

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참고문헌 (28)

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Regulation of DNA repair in the absence of classical non-homologous end joining

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Regulation of DNA repair in the absence of classical non-homologous end joining

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참고문헌 (28)

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