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Full-Text Articles in Molecular Biology

Dissecting The Functions Of Atr In Replication Fork Stability, Theonie Anastassiadis Jan 2017

Dissecting The Functions Of Atr In Replication Fork Stability, Theonie Anastassiadis

Publicly Accessible Penn Dissertations

Genome maintenance is required for cellular viability, and failure to preserve genomic integrity is associated with an increased risk of diseases, such as cancer. To ensure genomic stability, cells have checkpoints that control cell cycle progression in the event of DNA damage or incomplete DNA replication. The DNA replication checkpoint is regulated by the ATR-CHK1 pathway that stabilizes stalled replication forks and prevents their collapse into DNA double-strand breaks (DSBs). Two distinct models have been proposed to explain how ATR stabilizes stalled forks: 1) through local modulation of fork remodelers, such as SMARCAL1 inhibition, and 2) through inhibition of CDK-dependent ...


Defining Sites Of Replication Fork Collapse Caused By Atr Inhibition, Nishita Kalpendu Shastri Jan 2017

Defining Sites Of Replication Fork Collapse Caused By Atr Inhibition, Nishita Kalpendu Shastri

Publicly Accessible Penn Dissertations

DEFINING SITES OF REPLICATION FORK COLLAPSE CAUSED BY ATR INHIBITION

Nishita K. Shastri

Eric J. Brown

Replication stress, characterized by stalling of DNA replication and the accumulation of abnormal replication intermediates, has been linked to the genomic instability observed in cancer. Previous studies have defined specific genomic sequences that are difficult to replicate to be more vulnerable to replication-associated breaks and rearrangements. However, many of these sequences have been identified through indirect and potentially biased approaches. To identify DNA sequences that contribute to replication-associated genomic instability, I will describe genome-wide screens I have performed to determine the location, sequence, and ...