Crosstalk between chromatin state and ATM signalling in DNA damage-induced transcription stress

Area of Science:

• Molecular Biology
• Cellular Biology
• Genomics

Background:

• The DNA Damage Response (DDR) is crucial for maintaining genomic stability.
• A link exists between chromatin structure and DDR signaling pathways.
• Mechanisms of this interplay during transcription-blocking DNA damage are not fully understood.

Purpose of the Study:

• To investigate the interplay between chromatin modifications and DDR signaling in response to transcription-blocking DNA lesions.
• To elucidate the molecular mechanisms connecting RNA polymerase II stalling to DDR activation.

Main Methods:

• Analysis of chromatin acetylation and histone modifications.
• Investigation of RNA:DNA hybrid (R-loop) formation.
• Assessment of ATM signaling pathway activation and downstream kinase activity (p38MAPK/MSK1).

Main Results:

• Stalled RNA polymerase II at DNA lesions induces local chromatin acetylation via p300.
• Chromatin relaxation promotes spliceosome dissociation and R-loop formation, activating ATM.
• ATM activation leads to H2A.X phosphorylation and p38MAPK/MSK1-dependent H3S10 phosphorylation, altering chromatin conformation.

Conclusions:

• Transcription-blocking DNA lesions trigger a DDR pathway involving chromatin acetylation and R-loop formation.
• ATM signaling is modulated by chromatin state, and in turn, influences chromatin conformation.
• This cross-regulation between chromatin and ATM signaling is a key mechanism in the cellular response to transcription stress.