# The role of macroH2A variants in cancer and senescence

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2021 · $382,013

## Abstract

Project Summary
 The macroH2A1-type histone variants (which include macroH2A1.1 and macroH2A1.2) have roles in
tumor suppression, senescence, activation and repression of transcription, promotion of DNA repair and
suppression of the reprogramming of differentiated cells into stem cells. MacroH2As are typified by a
histone H2A-like region fused by a flexible linker to a C-terminal macrodomain, a ligand-binding domains
whose functions are modulated by binding to poly(ADP-ribose) produced by a family of poly(ADP-ribose)
polymerases. MacroH2A1 regulates the expression of genes found within its large chromatin domains which
can span hundreds of kilobases. MacroH2A1 also plays a critical role in regulating gene expression during
oncogene-induced senescence, an important tumor suppressive mechanisms. Interestingly, during
senescence an ER stress-dependent mechanism requiring the DNA damage signaling kinase ATM leads to
genome-wide changes in macroH2A1 genomic distribution which resemble that of cancer cells. Through
changes in its expression and/or alterations in its genomic localization, disruption of macroH2A1’s tumor
suppressive functions is common in cancer; alterations of macroH2A transcription and splicing have been
observed in a variety of cancers including those of lung, breast, colon, ovaries, endometrium, bladder,
testicles, and melanocytes. Consistently, macroH2A1 loss in primary cells is sufficient to trigger an
oncogenic gene expression profile.
 The overall goals of this project are to elucidate the function of macroH2A1in the regulation of gene
expression in normal and senescent cells and to determine how dysregulation of macroH2A1 function
contributes to alterations in gene expression that allow senescence-bypass and oncogenesis. A variety of
innovative reverse genetics, pharmacological and genome-wide approaches will be used in the pursuit of
these goals. The first aim will determine the mechanisms by which macroH2A1 variants regulate
transcription in normal and senescent cells. The second aim will determine the mechanism of ATM
activation and macroH2A1 mobilization in response to ER stress during senescence. The third aim will
determine the mechanism by with RNA Pol II elongation rate regulates macroH2A1 splicing. The knowledge
about macroH2A1-mediated regulation of gene expression, genomic localization and macroH2A1 splicing
regulation gained from this proposal will help to explain how macroH2A1 function becomes dysregulated
during oncogenesis.

## Key facts

- **NIH application ID:** 10132248
- **Project number:** 5R01CA155232-12
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** MATTHEW J GAMBLE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $382,013
- **Award type:** 5
- **Project period:** 2012-05-04 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10132248

## Citation

> US National Institutes of Health, RePORTER application 10132248, The role of macroH2A variants in cancer and senescence (5R01CA155232-12). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10132248. Licensed CC0.

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