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Degradation of 5hmC-marked stalled replication forks by APE1 causes genomic instability

  1. Author:
    Kharat,Suhas [ORCID]
    Ding, Xia [ORCID]
    Swaminathan, Divya [ORCID]
    Suresh, Akshey
    Singh, Manish
    Sengodan,Satheesh
    Burkett,Sandra [ORCID]
    Marks, Hanna [ORCID]
    Pamala, Chinmayi
    He,Yafeng [ORCID]
    Fox,Stephen [ORCID]
    Buehler, Eugen C [ORCID]
    Muegge,Kathrin
    Martin, Scott E
    Sharan,Shyam [ORCID]
  2. Author Address

    Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA., Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA., Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, MD 20850, USA., Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA. sharans@mail.nih.gov.,
    1. Year: 2020
    2. Date: Aug 18
    3. Epub Date: 2020 08 18
  1. Journal: Science signaling
    1. 13
    2. 645
    3. Pages: pii: eaba8091
  2. Type of Article: Article
  3. Article Number: eaba8091
  4. ISSN: 1945-0877
  1. Abstract:

    Synthetic lethality between poly(ADP-ribose) polymerase (PARP) inhibition and BRCA deficiency is exploited to treat breast and ovarian tumors. However, resistance to PARP inhibitors (PARPis) is common. To identify potential resistance mechanisms, we performed a genome-wide RNAi screen in BRCA2-deficient mouse embryonic stem cells and validation in KB2P1.21 mouse mammary tumor cells. We found that resistance to multiple PARPi emerged with reduced expression of TET2 (ten-eleven translocation), which promotes DNA demethylation by oxidizing 5-methylcytosine (5mC) to 5-hydroxymethycytosine (5hmC) and other products. TET2 knockdown in BRCA2-deficient cells protected stalled replication forks (RFs). Increasing 5hmC abundance induced the degradation of stalled RFs in KB2P1.21 and human cancer cells by recruiting the base excision repair-associated apurinic/apyrimidinic endonuclease APE1, independent of the BRCA2 status. TET2 loss did not affect the recruitment of the repair protein RAD51 to sites of double-strand breaks (DSBs) or the abundance of proteins associated with RF integrity. The loss of TET2, of its product 5hmC, and of APE1 recruitment to stalled RFs promoted resistance to the chemotherapeutic cisplatin. Our findings reveal a previously unknown role for the epigenetic mark 5hmC in maintaining the integrity of stalled RFs and a potential resistance mechanism to PARPi and cisplatin. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

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External Sources

  1. DOI: 10.1126/scisignal.aba8091
  2. PMID: 32817374
  3. WOS: 000561223700003
  4. PII : 13/645/eaba8091

Library Notes

  1. Fiscal Year: FY2019-2020
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