Non-specific chromosomal aberrations (CAs) are microscopically detected in about 1% of lymphocytes drawn from healthy persons. Causes of CAs in general population are not known but they may be related to risk of cancer. In view of the importance of the mitotic checkpoint machinery on maintaining chromosomal integrity we selected 9 variants in main checkpoint related genes (BUB1B, BUB3, MAD2L1, CENPF, ESPL1/separase, NEK2, PTTG1/securin, ZWILCH and ZWINT) for a genotyping study on samples from healthy individuals (N = 330 to 729) whose lymphocytes had an increased number of CAs compared to persons with a low number of CAs. Genetic variation in individual genes played a minor importance, consistent with the high conservation and selection pressure of the checkpoint system. However, gene pairs were significantly associated with CAs: PTTG1-ZWILCH and PTTG1-ZWINT. MAD2L1 and PTTG1 were the most common partners in any of the two-way interactions. The results suggest that interactions at the level of cohesin (PTTG1) and kinetochore function (ZWINT, ZWILCH and MAD2L1) contribute to the frequency of CAs, suggesting that gene variants at different checkpoint functions appeared to be required for the formation of CAs.

• Klíčová slova
• Chromosomal integrity, Cytogenetics, DNA double-stranded break, Spindle checkpoint,
• MeSH
• CDC geny * MeSH
• chromozomální aberace * MeSH
• dvouřetězcové zlomy DNA MeSH
• genetická variace * MeSH
• intracelulární signální peptidy a proteiny genetika   MeSH
• jaderné proteiny genetika   MeSH
• kontrolní body M fáze buněčného cyklu genetika   MeSH
• lidé MeSH
• lymfocyty chemie   patologie   MeSH
• Mad2 protein genetika   MeSH
• modely genetické MeSH
• proteiny buněčného cyklu genetika   MeSH
• sekurin genetika   MeSH
• zdraví dobrovolníci pro lékařské studie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• intracelulární signální peptidy a proteiny MeSH
• jaderné proteiny MeSH
• Mad2 protein MeSH
• MAD2L1 protein, human MeSH Prohlížeč
• pituitary tumor-transforming protein 1, human MeSH Prohlížeč
• proteiny buněčného cyklu MeSH
• sekurin MeSH
• Zwilch protein, human MeSH Prohlížeč
• ZWINT protein, human MeSH Prohlížeč

Error-free repair of DNA double-strand breaks (DSBs) is achieved by homologous recombination (HR), and BRCA1 is an important factor for this repair pathway. In the absence of BRCA1-mediated HR, the administration of PARP inhibitors induces synthetic lethality of tumour cells of patients with breast or ovarian cancers. Despite the benefit of this tailored therapy, drug resistance can occur by HR restoration. Genetic reversion of BRCA1-inactivating mutations can be the underlying mechanism of drug resistance, but this does not explain resistance in all cases. In particular, little is known about BRCA1-independent restoration of HR. Here we show that loss of REV7 (also known as MAD2L2) in mouse and human cell lines re-establishes CTIP-dependent end resection of DSBs in BRCA1-deficient cells, leading to HR restoration and PARP inhibitor resistance, which is reversed by ATM kinase inhibition. REV7 is recruited to DSBs in a manner dependent on the H2AX-MDC1-RNF8-RNF168-53BP1 chromatin pathway, and seems to block HR and promote end joining in addition to its regulatory role in DNA damage tolerance. Finally, we establish that REV7 blocks DSB resection to promote non-homologous end-joining during immunoglobulin class switch recombination. Our results reveal an unexpected crucial function of REV7 downstream of 53BP1 in coordinating pathological DSB repair pathway choices in BRCA1-deficient cells.

• MeSH
• 53BP1 MeSH
• adaptorové proteiny signální transdukční MeSH
• ATM protein antagonisté a inhibitory   metabolismus   MeSH
• buněčné linie MeSH
• chemorezistence genetika   MeSH
• chromatin metabolismus   MeSH
• chromozomální proteiny, nehistonové metabolismus   MeSH
• DNA vazebné proteiny metabolismus   MeSH
• dvouřetězcové zlomy DNA * MeSH
• histony metabolismus   MeSH
• intracelulární signální peptidy a proteiny metabolismus   MeSH
• jaderné proteiny metabolismus   MeSH
• lidé MeSH
• Mad2 protein nedostatek   genetika   metabolismus   MeSH
• myši MeSH
• PARP inhibitory * MeSH
• přesmyk imunoglobulinových tříd genetika   MeSH
• protein BRCA1 nedostatek   genetika   metabolismus   MeSH
• proteiny buněčného cyklu MeSH
• rekombinační oprava DNA * MeSH
• trans-aktivátory metabolismus   MeSH
• ubikvitinligasy metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 53BP1 MeSH
• adaptorové proteiny signální transdukční MeSH
• ATM protein MeSH
• chromatin MeSH
• chromozomální proteiny, nehistonové MeSH
• DNA vazebné proteiny MeSH
• H2AX protein, human MeSH Prohlížeč
• histony MeSH
• intracelulární signální peptidy a proteiny MeSH
• jaderné proteiny MeSH
• Mad2 protein MeSH
• MAD2L2 protein, human MeSH Prohlížeč
• Mad2l2 protein, mouse MeSH Prohlížeč
• MDC1 protein, human MeSH Prohlížeč
• PARP inhibitory * MeSH
• protein BRCA1 MeSH
• proteiny buněčného cyklu MeSH
• RNF168 protein, human MeSH Prohlížeč
• RNF8 protein, human MeSH Prohlížeč
• TP53BP1 protein, human MeSH Prohlížeč
• trans-aktivátory MeSH
• Trp53bp1 protein, mouse MeSH Prohlížeč
• ubikvitinligasy MeSH