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RAD51AP1 regulates ALT-HDR through chromatin-directed homeostasis of TERRA.
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.
Affiliation
  • Kaminski N; Department of Pharmacology and Chemical Biology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
  • Wondisford AR; Department of Pharmacology and Chemical Biology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
  • Kwon Y; Department of Biochemistry and Structural Biology, University of Texas Health Science Center, San Antonio, TX, USA.
  • Lynskey ML; Department of Pharmacology and Chemical Biology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
  • Bhargava R; Department of Pharmacology and Chemical Biology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
  • Barroso-González J; Department of Pharmacology and Chemical Biology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
  • García-Expósito L; Department of Pharmacology and Chemical Biology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
  • He B; Department of Biochemistry and Structural Biology, University of Texas Health Science Center, San Antonio, TX, USA; Department of Thoracic Surgery, Second Xiangya Hospital, Central South University, Changsha 410011, China.
  • Xu M; Department of Biological Sciences, Mellon College of Science, Carnegie Mellon University, Pittsburgh, PA, USA.
  • Mellacheruvu D; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA.
  • Watkins SC; Department of Cell Biology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
  • Modesti M; Cancer Research Center of Marseille, CNRS UMR7258, Inserm UMR1068, Aix Marseille Université U105, Institut Paoli Calmettes, 27 Boulevard Lei Roure CS30059, 13273 Marseille Cedex 09, France.
  • Miller KM; Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, The University of Texas at Austin, 2506 Speedway, Austin, TX 78712, USA.
  • Nesvizhskii AI; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA.
  • Zhang H; Department of Biological Sciences, Mellon College of Science, Carnegie Mellon University, Pittsburgh, PA, USA.
  • Sung P; Department of Biochemistry and Structural Biology, University of Texas Health Science Center, San Antonio, TX, USA.
  • O'Sullivan RJ; Department of Pharmacology and Chemical Biology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: osullivanr@upmc.edu.
Mol Cell ; 82(21): 4001-4017.e7, 2022 11 03.
Article in En | MEDLINE | ID: mdl-36265488
ABSTRACT
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Telomere Homeostasis / RNA, Long Noncoding Language: En Journal: Mol Cell Journal subject: BIOLOGIA MOLECULAR Year: 2022 Type: Article Affiliation country: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Telomere Homeostasis / RNA, Long Noncoding Language: En Journal: Mol Cell Journal subject: BIOLOGIA MOLECULAR Year: 2022 Type: Article Affiliation country: United States