2. Academic Validation
  3. SUMOylation of HNRNPA2B1 modulates RPA dynamics during unperturbed replication and genotoxic stress responses

SUMOylation of HNRNPA2B1 modulates RPA dynamics during unperturbed replication and genotoxic stress responses

  • Mol Cell. 2023 Jan 14;S1097-2765(23)00003-5. doi: 10.1016/j.molcel.2023.01.003.
Shouhai Zhu 1,  Jing Hou 2,  Huanyao Gao 3,  Qi Hu 4,  Jake A Kloeber 5,  Jinzhou Huang 1,  Fei Zhao 1,  Qin Zhou 1,  Kuntian Luo 1,  Zheming Wu 1,  Xinyi Tu 1,  Ping Yin 1,  Zhenkun Lou 6
Affiliations

Affiliations

  • 1 Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.
  • 2 Department of Breast Surgery, Guizhou Provincial People's Hospital, Guiyang, Guizhou 550002, China.
  • 3 Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
  • 4 Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.
  • 5 Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA; Mayo Clinic Medical Scientist Training Program, Mayo Clinic, Rochester, MN 55905, USA.
  • 6 Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: lou.zhenkun@mayo.edu.
PMID: 36702126 DOI: 10.1016/j.molcel.2023.01.003
Abstract

Replication protein A (RPA) is a major regulator of eukaryotic DNA metabolism involved in multiple essential cellular processes. Maintaining appropriate RPA dynamics is crucial for cells to prevent RPA exhaustion, which can lead to replication fork breakage and replication catastrophe. However, how cells regulate RPA availability during unperturbed replication and in response to stress has not been well elucidated. Here, we show that HNRNPA2B1SUMO functions as an endogenous inhibitor of RPA during normal replication. HNRNPA2B1SUMO associates with RPA through recognizing the SUMO-interacting motif (SIM) of RPA to inhibit RPA accumulation at replication forks and impede local ATR activation. Declining HNRNPA2SUMO induced by DNA damage will release nuclear soluble RPA to localize to chromatin and enable ATR activation. Furthermore, we characterize that HNRNPA2B1 hinders homologous recombination (HR) repair via limiting RPA availability, thus conferring sensitivity to PARP inhibitors. These findings establish HNRNPA2B1 as a critical player in RPA-dependent surveillance networks.

Keywords

ATR; ATRIP; DNA damage; HNRNPA2B1; RPA; SUMOylation; breast cancer; homologous recombination; replication stress.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-108702
    99.90%, SUMO-Activating Enzyme Inhibitor