1. Academic Validation
  2. Oncohistone Mutations Occur at Functional Sites of Regulatory ADP-Ribosylation

Oncohistone Mutations Occur at Functional Sites of Regulatory ADP-Ribosylation

  • Cancer Res. 2022 Jul 5;82(13):2361-2377. doi: 10.1158/0008-5472.CAN-22-0742.
Dan Huang 1 2 3 Cristel V Camacho 1 2 Sara Martire 2 4 Anusha Nagari 1 2 5 Rohit Setlem 1 2 5 Xuan Gong 1 2 Andrea D Edwards 1 2 Shu-Ping Chiu 1 2 Laura A Banaszynski 2 4 W Lee Kraus 1 2
Affiliations

Affiliations

  • 1 Laboratory of Signaling and Gene Regulation, Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, Texas.
  • 2 Division of Basic Research, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas.
  • 3 Department of Cardiology, Clinical Center for Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China.
  • 4 Laboratory of Chromatin Biology, Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, Texas.
  • 5 Computational Core Facility, Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, Texas.
Abstract

Recent studies have identified cancer-associated mutations in histone genes that lead to the expression of mutant versions of core histones called oncohistones. Many oncohistone mutations occur at Asp and Glu residues, two Amino acids known to be ADP-ribosylated (ADPRylated) by PARP1. We screened 25 Glu or Asp oncohistone mutants for their effects on cell growth in breast and ovarian Cancer cells. Ectopic expression of six mutants of three different core histones (H2B, H3, and H4) altered cell growth in at least two different cell lines. Two of these sites, H2B-D51 and H4-D68, were indeed sites of ADPRylation in wild-type (unmutated) histones, and mutation of these sites inhibited ADPRylation. Mutation of H2B-D51 dramatically altered chromatin accessibility at enhancers and promoters, as well as gene expression outcomes, whereas mutation of H4-D68 did not. Additional biochemical, cellular, proteomic, and genomic analyses demonstrated that ADPRylation of H2B-D51 inhibits p300-mediated acetylation of H2B at many Lys residues. In breast Cancer cell xenografts in mice, H2B-D51A promoted tumor growth, but did not confer resistance to the cytotoxic effects of PARP inhibition. Collectively, these results demonstrate that functional Asp and Glu ADPRylation sites on histones are mutated in cancers, allowing Cancer cells to escape the growth-regulating effects of post-translational modifications via distinct mechanisms.

Significance: This study identifies cancer-driving mutations in histones as sites of PARP1-mediated ADP-ribosylation in breast and ovarian cancers, providing a molecular pathway by which cancers may subvert the growth-regulating effects of PARP1.

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