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RAD51AP1 regulates ALT-HDR through chromatin-directed homeostasis of TERRA

Alternative lengthening of telomeres (ALT) is a homology-directed repair (HDR) mechanism of telomere elongation that controls proliferation in subsets of aggressive cancer. Recent studies have revealed that telomere repeat-containing RNA (TERRA) promotes ALT-associated HDR (ALT-HDR). Here, we report...

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Published in:Molecular cell 2022-11, Vol.82 (21), p.4001-4017.e7
Main Authors: Kaminski, Nicole, Wondisford, Anne R., Kwon, Youngho, Lynskey, Michelle Lee, Bhargava, Ragini, Barroso-González, Jonathan, García-Expósito, Laura, He, Boxue, Xu, Meng, Mellacheruvu, Dattatreya, Watkins, Simon C., Modesti, Mauro, Miller, Kyle M., Nesvizhskii, Alexey I., Zhang, Huaiying, Sung, Patrick, O’Sullivan, Roderick J.
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creator Kaminski, Nicole
Wondisford, Anne R.
Kwon, Youngho
Lynskey, Michelle Lee
Bhargava, Ragini
Barroso-González, Jonathan
García-Expósito, Laura
He, Boxue
Xu, Meng
Mellacheruvu, Dattatreya
Watkins, Simon C.
Modesti, Mauro
Miller, Kyle M.
Nesvizhskii, Alexey I.
Zhang, Huaiying
Sung, Patrick
O’Sullivan, Roderick J.
description Alternative lengthening of telomeres (ALT) is a homology-directed repair (HDR) mechanism of telomere elongation that controls proliferation in subsets of aggressive cancer. Recent studies have revealed that telomere repeat-containing RNA (TERRA) promotes ALT-associated HDR (ALT-HDR). Here, we report that RAD51AP1, a crucial ALT factor, interacts with TERRA and utilizes it to generate D- and R-loop HR intermediates. We also show that RAD51AP1 binds to and might stabilize TERRA-containing R-loops as RAD51AP1 depletion reduces R-loop formation at telomere DNA breaks. Proteomic analyses uncover a role for RAD51AP1-mediated TERRA R-loop homeostasis in a mechanism of chromatin-directed suppression of TERRA and prevention of transcription-replication collisions (TRCs) during ALT-HDR. Intriguingly, we find that both TERRA binding and this non-canonical function of RAD51AP1 require its intrinsic SUMO-SIM regulatory axis. These findings provide insights into the multi-contextual functions of RAD51AP1 within the ALT mechanism and regulation of TERRA. [Display omitted] •RAD51AP1 and TERRA interact and stimulate the formation of D and R loops•TERRA R-loops generated by RAD51AP1 regulate repressive chromatin at telomeres•RAD51AP1 protects telomeric regions from transcription-replication collisions Kaminski et al. show the cooperative roles of RAD51AP1 and TERRA in generating HR intermediates during ALT-HDR. Proteomic analyses uncover that RAD51AP1 binding of R-loops might serve to maintain chromatin that suppresses TERRA and prevents transcription-replication collisions (TRCs) during ALT-HDR.
doi_str_mv 10.1016/j.molcel.2022.09.025
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[Display omitted] •RAD51AP1 and TERRA interact and stimulate the formation of D and R loops•TERRA R-loops generated by RAD51AP1 regulate repressive chromatin at telomeres•RAD51AP1 protects telomeric regions from transcription-replication collisions Kaminski et al. show the cooperative roles of RAD51AP1 and TERRA in generating HR intermediates during ALT-HDR. Proteomic analyses uncover that RAD51AP1 binding of R-loops might serve to maintain chromatin that suppresses TERRA and prevents transcription-replication collisions (TRCs) during ALT-HDR.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>36265488</pmid><doi>10.1016/j.molcel.2022.09.025</doi><tpages>-932</tpages><orcidid>https://orcid.org/0000-0002-0289-0911</orcidid><orcidid>https://orcid.org/0000-0002-4964-331X</orcidid><oa>free_for_read</oa></addata></record>
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ispartof Molecular cell, 2022-11, Vol.82 (21), p.4001-4017.e7
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1097-4164
language eng
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source BACON - Elsevier - GLOBAL_SCIENCEDIRECT-OPENACCESS
subjects ALT
cancer
chromatin
Chromatin - genetics
Homeostasis
homology-directed repair
Life Sciences
Proteomics
RAD51AP1
RNA, Long Noncoding - genetics
telomere
Telomere - genetics
Telomere - metabolism
Telomere Homeostasis
TERRA
transcription
title RAD51AP1 regulates ALT-HDR through chromatin-directed homeostasis of TERRA
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