Repair of base damage within break-induced replication intermediates promotes kataegis associated with chromosome rearrangements

Rajula Elango; Beth Osia; Victoria Harcy; Ewa Malc; Piotr A Mieczkowski; Steven A Roberts; Anna Malkova

doi:10.1093/nar/gkz651

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Repair of base damage within break-induced replication intermediates promotes kataegis associated with chromosome rearrangements

Journal article

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Peer reviewed

Repair of base damage within break-induced replication intermediates promotes kataegis associated with chromosome rearrangements

Rajula Elango, Beth Osia, Victoria Harcy, Ewa Malc, Piotr A Mieczkowski, Steven A Roberts and Anna Malkova

Nucleic acids research, Vol.47(18), pp.9666-9684

10/10/2019

DOI: 10.1093/nar/gkz651

PMCID: PMC6765108

PMID: 31392335

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Abstract

Break induced replication (BIR) is a double strand break repair pathway that can promote genetic instabilities similar to those observed in cancer. Instead of a replication fork, BIR is driven by a migration bubble where asynchronous synthesis between leading and lagging strands leads to accumulation of single-stranded DNA (ssDNA) that promotes mutation. However, the details of the mechanism of mutagenesis, including the identity of the participating proteins, remain unknown. Using yeast as a model, we demonstrate that mutagenic ssDNA is formed at multiple positions along the BIR track and that Pol ζ is responsible for the majority of both spontaneous and damage-induced base substitutions during BIR. We also report that BIR creates a potent substrate for APOBEC3A (A3A) cytidine deaminase that can promote formation of mutation clusters along the entire track of BIR. Finally, we demonstrate that uracil glycosylase initiates the bypass of DNA damage induced by A3A in the context of BIR without formation of base substitutions, but instead this pathway frequently leads to chromosomal rearrangements. Together, the expression of A3A during BIR in yeast recapitulates the main features of APOBEC-induced kataegis in human cancers, suggesting that BIR might represent an important source of these hyper-mutagenic events.

Genome Integrity, Repair and

Details

Title: Subtitle: Repair of base damage within break-induced replication intermediates promotes kataegis associated with chromosome rearrangements
Creators: Rajula Elango - , Iowa City, IA 52245, , Pullman, WA 99164, , Chapel Hill, NC 27599
Beth Osia - , Iowa City, IA 52245, , Pullman, WA 99164, , Chapel Hill, NC 27599
Victoria Harcy - , Iowa City, IA 52245, , Pullman, WA 99164, , Chapel Hill, NC 27599
Ewa Malc - , Iowa City, IA 52245, , Pullman, WA 99164, , Chapel Hill, NC 27599
Piotr A Mieczkowski - , Iowa City, IA 52245, , Pullman, WA 99164, , Chapel Hill, NC 27599
Steven A Roberts - , Iowa City, IA 52245, , Pullman, WA 99164, , Chapel Hill, NC 27599
Anna Malkova - , Iowa City, IA 52245, , Pullman, WA 99164, , Chapel Hill, NC 27599
Resource Type: Journal article
Publication Details: Nucleic acids research, Vol.47(18), pp.9666-9684
DOI: 10.1093/nar/gkz651
PMID: 31392335
PMCID: PMC6765108
NLM abbreviation: Nucleic Acids Res
ISSN: 0305-1048
eISSN: 1362-4962
Publisher: Oxford University Press
Grant note: R01CA218112 / ; ; 1R35GM127006 / ; ; R00ES022633 / ; ;
Language: English
Date published: 10/10/2019
Academic Unit: Biology
Record Identifier: 9984217528002771

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