DNA NHEJ (non-homologous end-joining) is the major DNA DSB (double-strand break) repair pathway in mammalian cells. Although NHEJ-defective cell lines show marked DSB-repair defects, cells defective in ATM (ataxia telangiectasia mutated) repair most DSBs normally. Thus NHEJ functions independently of ATM signalling. However, ∼15% of radiation-induced DSBs are repaired with slow kinetics and require ATM and the nuclease Artemis. DSBs persisting in the presence of an ATM inhibitor, ATMi, localize to heterochromatin, suggesting that ATM is required for repairing DSBs arising within or close to heterochromatin. Consistent with this, we show that siRNA (small interfering RNA) of key heterochromatic proteins, including KAP-1 [KRAB (Krüppel-associated box) domain-associated protein 1], HP1 (heterochromatin protein 1) and HDAC (histone deacetylase) 1/2, relieves the requirement for ATM for DSB repair. Furthermore, ATMi addition to cell lines with genetic alterations that have an impact on heterochromatin, including Suv39H1/2 (suppressor of variegation 3–9 homologue 1/2)-knockout, ICFa (immunodeficiency, centromeric region instability, facial anomalies syndrome type a) and Hutchinson–Guilford progeria cell lines, fails to have an impact on DSB repair. KAP-1 is a highly dose-dependent, transient and ATM-specific substrate, and mutation of the ATM phosphorylation site on KAP-1 influences DSB repair. Collectively, the findings show that ATM functions to overcome the barrier to DSB repair posed by heterochromatin. However, even in the presence of ATM, γ-H2AX (phosphorylated histone H2AX) foci form on the periphery rather than within heterochromatic centres. Finally, we show that KAP-1's association with heterochromatin is diminished as cells progress through mitosis. We propose that KAP-1 is a critical heterochromatic factor that undergoes specific modifications to promote DSB repair and mitotic progression in a manner that allows localized and transient chromatin relaxation, but precludes significant dismantling of the heterochromatic superstructure.
Skip Nav Destination
Article navigation
June 2009
-
Cover Image
Cover Image
- PDF Icon PDF LinkFront Matter
- PDF Icon PDF LinkTable of Contents
Conference Article|
May 20 2009
The impact of heterochromatin on DSB repair Available to Purchase
Aaron A. Goodarzi;
Aaron A. Goodarzi
1Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, U.K.
Search for other works by this author on:
Angela T. Noon;
Angela T. Noon
1Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, U.K.
Search for other works by this author on:
Penny A. Jeggo
Penny A. Jeggo
1
1Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, U.K.
1To whom correspondence should be addressed (email [email protected]).
Search for other works by this author on:
Publisher: Portland Press Ltd
Received:
December 08 2008
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2009 Biochemical Society
2009
Biochem Soc Trans (2009) 37 (3): 569–576.
Article history
Received:
December 08 2008
Citation
Aaron A. Goodarzi, Angela T. Noon, Penny A. Jeggo; The impact of heterochromatin on DSB repair. Biochem Soc Trans 1 June 2009; 37 (3): 569–576. doi: https://doi.org/10.1042/BST0370569
Download citation file:
Sign in
Don't already have an account? Register
Sign in to your personal account
You could not be signed in. Please check your email address / username and password and try again.
Could not validate captcha. Please try again.
Biochemical Society Member Sign in
Sign InSign in via your Institution
Sign in via your InstitutionGet Access To This Article
Get Email Alerts
Open Access for all
We offer compliant routes for all authors from 2025. With library support, there will be no author nor reader charges in 5 journals. Check here |
![]() |