Role of HELB in the Replication Stress Response

Summary
Accurate and complete replication of the genome is essential for both proliferation and genomic stability.
Genomic DNA is constantly under assault from both exogenous and endogenous agents. The resulting DNA
lesions can cause stalling of the replication fork and activation of the replication stress response (RSR). This
activates a group of proteins that protect and restart the replication fork so that genomic integrity is maintained.
Incorrect repair can lead to cancer and aging, and defects in the RSR predispose individuals to develop cancer.
Our overall goal is to define the molecular mechanisms that protect the genome during replication stress. We
have discovered that DNA Helicase B (HELB) protects stalled replication forks from aberrant degradation by
nucleases and promotes replication restart. This is consistent with data showing reduced recovery from
replication stress with HELB knockdown; however, the mechanism by which HELB promotes recovery from
replication stress is unknown. In addition, we have found that HELB enhances replication through G-quadruplex
(G4) structures, suggesting that HELB may enable the replication fork to progress through difficult to replicate
sites. Since replication stalling can result in epigenetic instability, HELB may be involved in epigenetic
maintenance in addition to genomic maintenance. HELB has also been implicated in initiation of DNA replication
and regulation of end resection in homologous recombination (HR). Due to its varied roles in multiple processes,
regulation of HELB activity is likely required. Indeed, we have evidence that HELB activity is regulated by post-
translational modifications (PTMs). We hypothesize that HELB maintains genomic and epigenetic integrity by
protecting nascent DNA from degradation, aiding in replication restart, and assisting in replication through difficult
sites. We will test this hypothesis through the following Specific Aims: (1) Ascertain the role of HELB in protection
and restart of stalled DNA replication forks, (2) Determine the function of HELB in replication through difficult to
replicate regions of the genome, and (3) Delineate the role of HELB PTMs and protein-protein interactions (PPIs)
in the replication stress response.

Grant Number: 5P20GM121293-09
NIH Institute/Center: NIH
Principal Investigator: Alicia Byrd