# Arsenic carcinogenesis and disruption of histone variant H3.3 assembly

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $557,241

## Abstract

PROJECT SUMMARY
Arsenic has been identified as a prominent causal agent in skin, lung, bladder, and liver cancers. Arsenic
contamination impacts hundreds of millions of people in the world. The carcinogenicity of arsenic coupled with
an alarmingly large number of people exposed creates an urgency for studying and understanding its
carcinogenic mechanisms so effective therapeutic intervention can be initiated. Unlike most other genes,
canonical histone messenger RNAs (mRNAs) such as histone H3.1 mRNA do not end with a poly(A) tail,
instead they have a stem-loop structure at their 3’ end. Stem-loop binding protein (SLBP) attaches to the stem-
loop RNA structure that is required for 3’-processing of the canonical histone mRNA. Previously we found that
arsenic exposure downregulates SLBP levels, allowing the canonical histone H3.1 mRNA to acquire a poly(A)
tail. Polyadenylation of H3.1 mRNA appeared to be carcinogenic, since it induced transcriptional deregulation,
cell cycle arrest, and genomic instability, and facilitated anchorage-independent cell growth and tumor
formation in nude mice. These effects were likely resulting from disruption of variant histone H3.3 assembly,
because genome-wide histone mapping showed that polyadenylation of H3.1 mRNA compromised the H3.3
assembly at the sites critical for transcription, cell identity, and heterochromatin spreading. H3.3 plays
important roles in transcription, efficient DNA damage repair, proper segregation of chromosomes, and
development. The knockdown of H3.3, which mimics disruption of H3.3 assembly, induced cell transformation.
Furthermore, H3.3 mutants have been linked to various type of cancers, underscoring importance of H3.3 in
carcinogenesis. Based on these observations, we hypothesize that disruption of H3.3 assembly resulting
from polyadenylation of canonical histone H3.1 mRNA is a significant contributor to arsenic-induced
carcinogenesis. To test this hypothesis, we will determine the mechanisms by which polyadenylated
canonical histone H3.1 mRNA disrupts assembly of the variant H3.3 in Aim 1, determine whether defective
H3.3 assembly is responsible for arsenic-induced aberrant transcription, cell cycle arrest as well as genomic
instability in Aim 2, and determine the role for disruption of H3.3 assembly in arsenic-induced cell
transformation and explore whether arsenic exposure disrupts H3.3 assembly in vivo in Aim 3. The significance
and innovation of these studies lie in the potential to reveal disruption of H3.3 assembly as a novel mechanism
of arsenic-induced carcinogenesis.

## Key facts

- **NIH application ID:** 10009347
- **Project number:** 5R01ES030583-02
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Max Costa
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $557,241
- **Award type:** 5
- **Project period:** 2019-09-06 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10009347

## Citation

> US National Institutes of Health, RePORTER application 10009347, Arsenic carcinogenesis and disruption of histone variant H3.3 assembly (5R01ES030583-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10009347. Licensed CC0.

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