# Mechanisms of heterochromatin replication

> **NIH NIH R01** · CORNELL UNIVERSITY · 2021 · $301,059

## Abstract

PROJECT SUMMARY
Heterochromatic domains, such as centromeres, telomeres and other satellite DNA, pose a major challenge for
DNA replication. Compacted chromatin is thought to inhibit replication initiation and obstruct progression of the
replication machinery. Not surprisingly, recent analyses of various somatic and cancer cells have revealed that
repressive chromatin is associated with regions of late replication and high mutation density. Little, however, is
known about the molecular mechanisms that control and facilitate DNA replication at heterochromatic domains.
Of importance, cancer cells may harness these mechanisms to facilitate heterochromatin replication and
sustain their increased proliferative demands. For example, overexpression of KDM4A/JMJD2, a demethylase
that removes the heterochromatic mark H3K9 tri-methylation, enables chromatin de-compaction and
accelerated replication in ovarian cancers. Strikingly, KDM4A overexpression also resulted in copy gain of
specific genomic loci often amplified in ovarian cancers and multiple myeloma, further strengthening the link
between de-regulated heterochromatin replication and genomic instability. These observations highlight the
need to elucidate the mechanisms required for proper heterochromatin replication so as to understand
fundamental aspects of genome maintenance and the control of cell proliferation.
 This proposal is centered on METTL13 (Methyltransferase-like 13), a member of a poorly understood
family of proteins containing putative SAM (S-adenosylmethionine)-binding domains. While METTL13 was
found amplified and overexpressed in cancers, virtually nothing was previously known about its cellular
functions. Preliminary results presented here provide the first insights on how METTL13 sustains cell
proliferation, revealing crucial roles in DNA replication and chromatin dynamics. More specifically, we find that
METTL13 is a novel key mediator of heterochromatin replication that is particularly important for replication of
centromeres. To the best of our knowledge this is the first described regulator of human centromere
replication timing. This proposal will combine cutting edge genomic and proteomic techniques with
biochemical and cell biological approaches to dissect the action of METTL13 and establish its role in
controlling chromatin dynamics, DNA replication and genome integrity. Generated results will reveal a
fundamental mechanism of heterochromatin replication and replication timing control, and will establish novel
drug targets for modulating chromatin dynamics and the proliferative capacity of cancer cells.

## Key facts

- **NIH application ID:** 10078281
- **Project number:** 5R01GM123018-04
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Marcus Smolka
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $301,059
- **Award type:** 5
- **Project period:** 2018-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10078281

## Citation

> US National Institutes of Health, RePORTER application 10078281, Mechanisms of heterochromatin replication (5R01GM123018-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10078281. Licensed CC0.

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