Project Details
Description
Project Summary
Robust and tightly regulated DNA repair is critical to maintain genome stability and prevent disease development.
Eukaryotic DNA is packaged into chromatin that has a profound, yet not well understood regulatory influence on
DNA repair, replication and genome maintenance. There is a fundamental gap in understanding how DNA repair
pathways are regulated and coordinated within structurally diverse chromatin, and across the heterogeneous
genomic landscape. The HELLS (Helicase Lymphoid Specific) is a poorly understood chromatin-associated
protein, with an emerging new role in genome maintenance. Mouse HELLS is essential for gametogenesis and
proper development of the immune system. Mutations in human HELLS cause severe immunodeficiency
syndrome ICF (Immunodeficiency Centromeric Instability Facial anomalies). Despite substantial progress in
understanding the molecular functions of the mammalian HELLS in DNA methylation and chromatin remodeling,
its role in DNA repair and genome maintenance is poorly understood and remains elusive. The unresolved
questions remain whether HELLS regulates multiple DNA repair pathways, and whether it has specialized roles
in the repair and maintenance of a distinct genomic loci or domains. We have established and validated fungal
model, Neurospora crassa to advance the fundamental understanding of HELLS-mediated mechanisms of
genome stability. Our studies reveal a new, previously unrecognized link between HELLS proteins and cellular
responses to DNA alkylation damage in fungal and human cells. We hypothesize that HELLS protects cells form
alkylation-induced toxicity and plays important roles in the repair and stability of the constitutive heterochromatin
domains. This hypothesis is founded based on a strong preliminary data in the fungal model Neurospora and in
human cells demonstrating that cells deficient in HELLS exhibit sensitivity to DNA alkylation damage and are
deficient in the repair of the constitutive heterochromatin. In addition, we discovered that loss of fungal WDR76
protein in HELLS mutant cells leads to the synthetic rescue of the alkylation sensitivity phenotype, implying that
WDR76 acts as genetic suppressor of HELLS deficiency. In Aim 1 we will determine the role of fungal and human
HELLS remodelers in the repair of alkylation DNA damage. In Aim 2 we will define precise genomic and
chromatin contexts that depend on HELLS for genome maintenance. In Aim 3 we will determine the functional
relationship between HELLS and WDR76, a WD40 protein implicated in response to DNA alkylation. Successful
completion of the proposed research will define HELLS-mediated mechanisms of genome maintenance, and
identify additional regulators and pathways cooperating with HELLS in protecting the cells from detrimental
consequences of genotoxic stress. These studies will provide important insights into the origin of the disease-
causing chromosomal rearrangements and breaks found in many human diseases, including the ICF syndrome.
Status | Active |
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Effective start/end date | 9/1/21 → 5/31/24 |
Funding
- National Institute of General Medical Sciences: $330,898.00
- National Institute of General Medical Sciences: $143,343.00
- National Institute of General Medical Sciences: $346,281.00
- National Institute of General Medical Sciences: $23,891.00
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