Break-induced replication orchestrates resection-dependent template switching

Tianpeng Zhang, Yashpal Rawal, Haoyang Jiang, Youngho Kwon, Patrick Sung and Roger A. Greenberg ()
Additional contact information
Tianpeng Zhang: University of Pennsylvania
Yashpal Rawal: University of Texas Health Science Center at San Antonio
Haoyang Jiang: University of Pennsylvania
Youngho Kwon: University of Texas Health Science Center at San Antonio
Patrick Sung: University of Texas Health Science Center at San Antonio
Roger A. Greenberg: University of Pennsylvania

Nature, 2023, vol. 619, issue 7968, 201-208

Abstract: Abstract Break-induced telomere synthesis (BITS) is a RAD51-independent form of break-induced replication that contributes to alternative lengthening of telomeres1,2. This homology-directed repair mechanism utilizes a minimal replisome comprising proliferating cell nuclear antigen (PCNA) and DNA polymerase-δ to execute conservative DNA repair synthesis over many kilobases. How this long-tract homologous recombination repair synthesis responds to complex secondary DNA structures that elicit replication stress remains unclear3–5. Moreover, whether the break-induced replisome orchestrates additional DNA repair events to ensure processivity is also unclear. Here we combine synchronous double-strand break induction with proteomics of isolated chromatin segments (PICh) to capture the telomeric DNA damage response proteome during BITS1,6. This approach revealed a replication stress-dominated response, highlighted by repair synthesis-driven DNA damage tolerance signalling through RAD18-dependent PCNA ubiquitination. Furthermore, the SNM1A nuclease was identified as the major effector of ubiquitinated PCNA-dependent DNA damage tolerance. SNM1A recognizes the ubiquitin-modified break-induced replisome at damaged telomeres, and this directs its nuclease activity to promote resection. These findings show that break-induced replication orchestrates resection-dependent lesion bypass, with SNM1A nuclease activity serving as a critical effector of ubiquitinated PCNA-directed recombination in mammalian cells.

Date: 2023
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-023-06177-3 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:619:y:2023:i:7968:d:10.1038_s41586-023-06177-3

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-023-06177-3

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().