Abstract
Gene expression is a multi-step process which requires recruitment of several factors to promoters. One of the factors, Sen1p is an RNA/DNA helicase implicated in transcriptional termination and RNA processing in yeast. In the present study, we have identified a novel function of Sen1p that regulates the expression of ribonucleotide reductase RNR1 gene, which is essential for maintaining genomic integrity. Cells with mutation in the helicase domain or lacking N-terminal domain of Sen1p displayed a drastic decrease in the basal level transcription of RNR1 gene and showed enhanced sensitivity to various DNA damaging agents. Moreover, SEN1 mutants [Sen1-1 (G1747D), Sen1-2 (Δ1-975)] exhibited defects in DNA damage checkpoint activation. Surprisingly, CRT1 deletion in Sen1p mutants (Sen1-1, Sen1-2) was partly able to rescue the slow growth phenotype upon genotoxic stress. Altogether, our observations suggest that Sen1p is required for cell protection against DNA damage by regulating the expression of DNA repair gene RNR1. Thus, the misregulation of Sen1p regulated genes can cause genomic instability that may lead to neurological disorders and premature aging.
Highlights
In eukaryotic organisms, genomic integrity is constantly challenged by various intrinsic and extrinsic genotoxic stresses, which is monitored by sophisticated cellular protein networks known as DNA damage response (DDR)
Our studies indicate that Sen1p has a novel role in maintaining genomic integrity by regulating the expression of Ribonucleotide Reductase 1 (RNR1) and that mutations in Sen1p can lead to the misregulation of DNA repair genes which is the fundamental basis of several diseases including neurological disorders
SEN1 is an ortholog of human SETX, which has been implicated in neurological disorders like AOA and ALS [29,30]
Summary
Genomic integrity is constantly challenged by various intrinsic and extrinsic genotoxic stresses, which is monitored by sophisticated cellular protein networks known as DNA damage response (DDR). Eukaryotic cells respond to DNA damage by arresting the cell cycle and by inducing genes implicated in DNA damage repair [1]. Mec and Rad induce the transcription of a number of DNA repair genes [2]. The MEC1 and RAD53 genes are evolutionarily conserved, which link DNA damage and checkpoint control to various human disorders and cancer [3]. Genes encoding ribonucleotide reductase (RNR) are the best-studied transcriptional targets of DNA replication and damage which are regulated by Mec1/Rad checkpoint kinase pathway [4,5]. There are four RNR genes (RNR1, RNR2, RNR3 and RNR4) known to encode DNA repair proteins which are highly inducible upon DNA damage
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