Gross chromosomal rearrangements are prominent in human cancers, with specific cytogenetic abnormalities contributing to hematopoietic, thyroid, prostate, and lung malignancies. Although the genesis of such chromosomal aberrations is incompletely understood, there is now strong evidence that a particularly dangerous situation arises when DNA double strand breaks (DSBs) occur in proximity to active transcription. These findings suggest that maintenance of genome integrity necessitates coordination between DNA repair and local transcriptional events. We have reported that DSBs silence transcription on contiguous stretches of chromatin in cis to DNA damage sites. Silencing requires ATM kinase activity and histone H2A ubiquitylation. We have extended these findings by discovering that DSB associated SUMOylation is essential for DSB silencing. An interesting observation from these studies is that ATM dependent DSB silencing prevents transcription dependent chromatin movement, a function that may relate to genome integrity control. This proposal utilizes several novel approaches to address two principle questions related to the interplay between DSB chromatin alterations and transcription: (i) How do DSB dependent chromatin alterations contribute to transcriptional gene silencing in cis to DSBs? (ii) Do DSB chromatin alterations promote accurate DNA repair mechanisms by opposing RNAPII driven chromatin movement? Collectively, these questions will address fundamental issues in genome integrity and radiation biology that are related to communication between DSB chromatin responses and transcription.
Gross chromosomal rearrangements are prominent in human cancers, with specific cytogenetic abnormalities contributing to hematopoietic, thyroid, prostate, and lung malignancies. Although the genesis of such chromosomal aberrations is incompletely understood, there is now strong evidence that a particularly dangerous situation arises when DNA double strand breaks (DSBs) occur in proximity to active transcription. These findings suggest that maintenance of genome integrity necessitates coordination between DNA repair and local transcriptional events. This proposal will address fundamental issues in genome integrity and radiation biology that are related to communication between DSB chromatin responses and transcription.
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