ASH1L histone methyltransferase regulates the handoff between damage recognition factors in global-genome nucleotide excision repair

Chiara Balbo Pogliano,Zuzana Garajovà,Hanspeter Naegeli,Peter Rüthemann,Marco Gatti,Lorenza Penengo

doi:10.1038/s41467-017-01080-8

Chiara Balbo Pogliano, Zuzana Garajovà + Show 4 more

Open Access

https://doi.org/10.1038/s41467-017-01080-8

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Journal: Nature Communications	Publication Date: Nov 6, 2017
Citations: 24	License type: open-access

Affiliation: University of Zurich

Abstract

Global-genome nucleotide excision repair (GG-NER) prevents ultraviolet (UV) light-induced skin cancer by removing mutagenic cyclobutane pyrimidine dimers (CPDs). These lesions are formed abundantly on DNA wrapped around histone octamers in nucleosomes, but a specialized damage sensor known as DDB2 ensures that they are accessed by the XPC initiator of GG-NER activity. We report that DDB2 promotes CPD excision by recruiting the histone methyltransferase ASH1L, which methylates lysine 4 of histone H3. In turn, methylated H3 facilitates the docking of the XPC complex to nucleosomal histone octamers. Consequently, DDB2, ASH1L and XPC proteins co-localize transiently on histone H3-methylated nucleosomes of UV-exposed cells. In the absence of ASH1L, the chromatin binding of XPC is impaired and its ability to recruit downstream GG-NER effectors diminished. Also, ASH1L depletion suppresses CPD excision and confers UV hypersensitivity. These findings show that ASH1L configures chromatin for the effective handoff between damage recognition factors during GG-NER activity.

Highlights

Global-genome nucleotide excision repair (GG-NER) prevents ultraviolet (UV) light-induced skin cancer by removing mutagenic cyclobutane pyrimidine dimers (CPDs)
We describe the ASH1L histone methyltransferase as an auxiliary factor that, like DDB2, is indispensable for excision of CPD lesions
The generally accepted model is that DDB2 protein recognizes CPDs and delivers these lesions to XPC, which is the initiator of GG-NER activity[53]

Summary

Introduction

Global-genome nucleotide excision repair (GG-NER) prevents ultraviolet (UV) light-induced skin cancer by removing mutagenic cyclobutane pyrimidine dimers (CPDs). These lesions are formed abundantly on DNA wrapped around histone octamers in nucleosomes, but a specialized damage sensor known as DDB2 ensures that they are accessed by the XPC initiator of GG-NER activity. ASH1L depletion suppresses CPD excision and confers UV hypersensitivity These findings show that ASH1L configures chromatin for the effective handoff between damage recognition factors during GG-NER activity. D Excision of CPDs in HeLa cells treated 48 h before UV radiation (10 J m–2) with siRNA targeting ASH1L or SETD2, compared to transfections with siNC (n = 5, each experiment with 4 replicates, twotailed t-test).

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