With each round of replication, billions of DNA bases must be replicated accurately and completely to yield two identical copies of the genome that eventually result in two daughter cells. There are several obstacles to this process including damage from endogenous or exogenous sources, nucleotide depletion, and hard-to-replicate sequences in the DNA. Telomeres are repetitive, highly structured hard-to-replicate DNA sequences that cap the ends of chromosomes to prevent inappropriate DNA damage signaling. To ensure complete replication of the genome, a mechanism to resolve the structured DNA and promote replication through telomeres must exist. Our preliminary data indicates that the DNA damage response protein SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A-like1) acts as a component of this general pathway to promote genomic stability at telomeres. I hypothesize that SMARCAL1 is essential for telomere maintenance and regulation. To investigate this essential function of SMARCAL1, I propose two aims: (1) to fully characterize the extent of this novel SMARCAL1 function at telomeres and (2) to identify the mechanism of Smarcal1 localization to telomeres. I will combine genetic and biochemical approaches to complete these aims. Through the completion of these studies, I will participate in multiple training activities to prepare for a career as an independent research scientist.
Telomeres exist as highly structured DNA caps that protect the ends of linear chromosomes;however, this protective function often hinders necessary processes like DNA replication through inefficient telomere structure resolution. The DNA damage response protein SMARCAL1 has been implicated in the pathway of telomere structure dismantlement indicating a new function for this protein outside its activity in bulk chromatin. This proposal utilizes microscopy and several biochemical and genetic techniques to characterize the function of SMARCAL1 telomeres.
|Poole, Lisa A; Cortez, David (2017) Functions of SMARCAL1, ZRANB3, and HLTF in maintaining genome stability. Crit Rev Biochem Mol Biol 52:696-714|
|Poole, Lisa A; Zhao, Runxiang; Glick, Gloria G et al. (2015) SMARCAL1 maintains telomere integrity during DNA replication. Proc Natl Acad Sci U S A 112:14864-9|