POLQ suppresses genome instability and alterations in DNA repeat tract lengths

Liddiard, Kate ORCID: https://orcid.org/0000-0002-0953-1997, Aston-Evans, Alys N., Cleal, Kez, Hendrickson, Eric A. and Baird, Duncan M. ORCID: https://orcid.org/0000-0001-8408-5467 2022. POLQ suppresses genome instability and alterations in DNA repeat tract lengths. NAR Cancer 4 (3) , zcac020. 10.1093/narcan/zcac020

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Abstract

DNA polymerase theta (POLQ) is a principal component of the alternative non-homologous end-joining (ANHEJ) DNA repair pathway that ligates DNA double-strand breaks. Utilizing independent models of POLQ insufficiency during telomere-driven crisis, we found that POLQ–/– cells are resistant to crisis-induced growth deceleration despite sustaining inter-chromosomal telomere fusion frequencies equivalent to wild-type (WT) cells. We recorded longer telomeres in POLQ–/– than WT cells pre- and post-crisis, notwithstanding elevated total telomere erosion and fusion rates. POLQ–/– cells emerging from crisis exhibited reduced incidence of clonal gross chromosomal abnormalities in accordance with increased genetic heterogeneity. High-throughput sequencing of telomere fusion amplicons from POLQ-deficient cells revealed significantly raised frequencies of inter-chromosomal fusions with correspondingly depreciated intra-chromosomal recombinations. Long-range interactions culminating in telomere fusions with centromere alpha-satellite repeats, as well as expansions in HSAT2 and HSAT3 satellite and contractions in ribosomal DNA repeats, were detected in POLQ–/– cells. In conjunction with the expanded telomere lengths of POLQ–/– cells, these results indicate a hitherto unrealized capacity of POLQ for regulation of repeat arrays within the genome. Our findings uncover novel considerations for the efficacy of POLQ inhibitors in clinical cancer interventions, where potential genome destabilizing consequences could drive clonal evolution and resistant disease.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Additional Information:	The authors wish it to be known that, in their opinion, the last two authors should be regarded as Joint Senior Authors.
Publisher:	Oxford University Press
ISSN:	2632-8674
Funders:	Cancer Research UK
Date of First Compliant Deposit:	14 June 2022
Date of Acceptance:	10 June 2022
Last Modified:	07 Jun 2023 21:57
URI:	https://orca.cardiff.ac.uk/id/eprint/150500

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