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ATRX and RECQ5 define distinct homologous recombination subpathways

Elbakry, Amira ; Juhász, Szilvia ; Chan, Ki Choi ; Löbrich, Markus (2021):
ATRX and RECQ5 define distinct homologous recombination subpathways. (Publisher's Version)
In: Proceedings of the National Academy of Sciences of the United States of America, 118 (3), National Academy of Sciences, ISSN 0027-8424, e-ISSN 1091-6490,
DOI: 10.26083/tuprints-00018942,
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Item Type: Article
Origin: Secondary publication service
Status: Publisher's Version
Title: ATRX and RECQ5 define distinct homologous recombination subpathways
Language: English
Abstract:

Homologous recombination (HR) is an important DNA double-strand break (DSB) repair pathway that copies sequence information lost at the break site from an undamaged homologous template. This involves the formation of a recombination structure that is processed to restore the original sequence but also harbors the potential for crossover (CO) formation between the participating molecules. Synthesis-dependent strand annealing (SDSA) is an HR subpathway that prevents CO formation and is thought to predominate in mammalian cells. The chromatin remodeler ATRX promotes an alternative HR subpathway that has the potential to form COs. Here, we show that ATRX-dependent HR outcompetes RECQ5-dependent SDSA for the repair of most two-ended DSBs in human cells and leads to the frequent formation of COs, assessed by measuring sister chromatid exchanges (SCEs). We provide evidence that subpathway choice is dependent on interaction of both ATRX and RECQ5 with proliferating cell nuclear antigen. We also show that the subpathway usage varies among different cancer cell lines and compare it to untransformed cells. We further observe HR intermediates arising as ionizing radiation (IR)-induced ultra-fine bridges only in cells expressing ATRX and lacking MUS81 and GEN1. Consistently, damage-induced MUS81 recruitment is only observed in ATRX-expressing cells. Cells lacking BLM show similar MUS81 recruitment and IR-induced SCE formation as control cells. Collectively, these results suggest that the ATRX pathway involves the formation of HR intermediates whose processing is entirely dependent on MUS81 and GEN1 and independent of BLM. We propose that the predominant ATRX-dependent HR subpathway forms joint molecules distinct from classical Holliday junctions.

Journal or Publication Title: Proceedings of the National Academy of Sciences of the United States of America
Journal volume: 118
Number: 3
Publisher: National Academy of Sciences
Collation: 11 Seiten
Classification DDC: 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie
Divisions: 10 Department of Biology > Radiation Biology and DNA Repair
Date Deposited: 16 Aug 2021 12:18
Last Modified: 16 Aug 2021 12:18
DOI: 10.26083/tuprints-00018942
Corresponding Links:
URN: urn:nbn:de:tuda-tuprints-189429
URI: https://tuprints.ulb.tu-darmstadt.de/id/eprint/18942
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