Human DNA polymerase η promotes RNA-templated error-free repair of DNA double-strand breaks

Chakraborty, Anirban; Tapryal, Nisha; Islam, Azharul; Sarker, Altaf H.; Manohar, Kodavati; Mitra, Joy; Hegde, Muralidhar L.; Hazra, Tapas

doi:10.1016/j.jbc.2023.102991

Human DNA polymerase η promotes RNA-templated error-free repair of DNA double-strand breaks

Journal Article · Tue Feb 07 23:00:00 EST 2023 · Journal of Biological Chemistry

DOI:https://doi.org/10.1016/j.jbc.2023.102991· OSTI ID:2470846

Chakraborty, Anirban ^[1]; Tapryal, Nisha ^[1]; Islam, Azharul ^[1]; Sarker, Altaf H. ^[2]; Manohar, Kodavati ^[3]; Mitra, Joy ^[3]; Hegde, Muralidhar L. ^[3]; Hazra, Tapas ^[1]

University of Texas Medical Branch, Galveston, TX (United States)
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
The Houston Methodist Research Institute, TX (United States)

A growing body of evidence indicates that RNA plays a critical role in orchestrating DNA double-strand break repair (DSBR). Recently, we showed that homologous nascent RNA can be used as a template for error-free repair of double-strand breaks (DSBs) in the transcribed genome and to restore the missing sequence at the break site via the transcription-coupled classical nonhomologous end-joining (TC-NHEJ) pathway. TC-NHEJ is a complex multistep process in which a reverse transcriptase (RT) is essential for synthesizing the DNA strand from template RNA. However, the identity of the RT involved in the TC-NHEJ pathway remained unknown. Here, we report that DNA polymerase eta (Pol η), known to possess RT activity, plays a critical role in TC-NHEJ. We found that Pol η forms a multiprotein complex with RNAP II and other TC-NHEJ factors, while also associating with nascent RNA. Moreover, purified Pol η, along with DSBR proteins PNKP, XRCC4, and Ligase IV can fully repair RNA templated 3'-phosphate-containing gapped DNA substrate. In addition, we demonstrate here that Pol η deficiency leads to accumulation of R-loops and persistent strand breaks in the transcribed genes. Finally, we determined that, in Pol η depleted but not in control cells, TC-NHEJ-mediated repair was severely abrogated when a reporter plasmid containing a DSB with several nucleotide deletion within the E. coli lacZ gene was introduced for repair in lacZ-expressing mammalian cells. Thus, our data strongly suggest that RT activity of Pol η is required in error-free DSBR.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE; National Institutes of Health (NIH); US Army Research Office (ARO)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 2470846

Journal Information:: Journal of Biological Chemistry, Journal Name: Journal of Biological Chemistry Journal Issue: 3 Vol. 299; ISSN 0021-9258

Publisher:: American Society for Biochemistry and Molecular BiologyCopyright Statement

Country of Publication:: United States

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
Biochemistry & Molecular Biology
DNA polymerase eta
RNA-templated DNA polymerase activity
RNA-templated repair
double strand break repair
transcription-coupled NHEJ

Human DNA polymerase η promotes RNA-templated error-free repair of DNA double-strand breaks

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