# Repression of retrotransposable elements by the longevity gene SIRT6.

> **NIH NIH P01** · BROWN UNIVERSITY · 2020 · $364,200

## Abstract

PROJECT SUMMARY (PROJECT 3)
Genomic and epigenomic instability plays a contributing role in aging. Genomic instability arises from chemical
and physical damage to DNA as well as from errors in DNA replication and repair. Recently, activation of
endogenous retrotransposable elements has emerged as another major source of age-related genomic
instability. SIRT6 plays an important role in maintaining genomic stability by regulating DNA repair. Recent
studies by our laboratory demonstrated that SIRT6 has another function in maintaining genome stability by
repressing LINE-1 (L1) transposable elements. We showed that SIRT6 represses L1 by mono-ADP
ribosylating KAP1, which promotes its interaction with heterochromatin factor HP1. Sirt6 knockout mice display
premature aging with a lifespan of 3-4 weeks, associated with dramatic L1 activation. Remarkably, our
preliminary data suggests that repression of L1 retrotransposition extends lifespan of these mice. Upon DNA
damage SIRT6 vacates L1 promoters and relocalized to DNA damage sites. The dual function of SIRT6 in
DNA damage and L1 repression may provide a mechanism for age-related genomic instability. We
hypothesize that with aging SIRT6 relocalizes from L1 promoters to the sites of DNA damage and shortened
telomeres leading to L1 activation and genome destabilization. The goal of this project is to understand the
molecular mechanism of L1 repression by SIRT6 and to dissect the interplay between DNA damage, L1
activation and aging. We will pursue the following specific aims. (1) To determine the mechanism of L1
repression by SIRT6 on the molecular level we will identify the KAP1 amino acids mono-ADP-ribosylated by
SIRT6 and determine how this modification affects the binding and recruitment of other heterochromatin
factors to L1 promoters. In collaboration with Project 1 we will examine the interaction between SIRT6 and pRb
L1 repression pathways. (2) To understand the interplay between SIRT6 function in DNA repair and L1
repression we will perform ChIP-seq to determine SIRT6 localization in young and old mice and in human
fibroblasts under basal conditions and after DNA damage. To identify factors that regulate SIRT6 localization
on chromatin we will identify posttranslational modifications that direct SIRT6 to either L1 promoters or DNA
damage sites. (3) To examine the contribution of L1 activation to the aging process we will treat wild type,
Sirt6-late onset, brain-specific, and full body knockout mice with reverse transcriptase inhibitors and test
whether the treatment alleviates aging-related phenotypes (with Core C). In collaboration with Core B we will
perform TIP-seq or single-cell TIP-seq on the Sirt6 knockout mice to quantify the retrotransposition events
before and after treatment. To determine which molecular functions of SIRT6 are involved in longevity we will
breed Sirt6 knockout mice with mice harboring SIRT6 separation of function mutations. Finally, we will
collaborate with Project 2 to ...

## Key facts

- **NIH application ID:** 9956960
- **Project number:** 5P01AG051449-05
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** Vera Gorbunova
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $364,200
- **Award type:** 5
- **Project period:** — → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9956960

## Citation

> US National Institutes of Health, RePORTER application 9956960, Repression of retrotransposable elements by the longevity gene SIRT6. (5P01AG051449-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9956960. Licensed CC0.

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