Unique and important consequences of RECQ1 deficiency in mammalian cells - PubMed (original) (raw)
Unique and important consequences of RECQ1 deficiency in mammalian cells
Sudha Sharma et al. Cell Cycle. 2008.
Abstract
Five members of the RecQ subfamily of DEx-H-containing DNA helicases have been identified in both human and mouse, and mutations in BLM, WRN, and RECQ4 are associated with human diseases of premature aging, cancer, and chromosomal instability. Although a genetic disease has not been linked to RECQ1 mutations, RECQ1 helicase is the most highly expressed of the human RecQ helicases, suggesting an important role in cellular DNA metabolism. Recent advances have elucidated a unique role of RECQ1 to suppress genomic instability. Embryonic fibroblasts from RECQ1-deficient mice displayed aneuploidy, chromosomal instability, and increased load of DNA damage.(1) Acute depletion of human RECQ1 renders cells sensitive to DNA damage and results in spontaneous gamma-H2AX foci and elevated sister chromatid exchanges, indicating aberrant repair of DNA breaks.(2) Consistent with a role in DNA repair, RECQ1 relocalizes to irradiation-induced nuclear foci and associates with chromatin.(2) RECQ1 catalytic activities(3) and interactions with DNA repair proteins(2,4,5) are likely to be important for its molecular functions in genome homeostasis. Collectively, these studies provide the first evidence for an important role of RECQ1 to confer chromosomal stability that is unique from that of other RecQ helicases and suggest its potential involvement in tumorigenesis.
Figures
Figure 1
Reduced cell growth and elevated sister chromatid exchange in RECQ1-depleted cells. (A) Proliferation of HeLa cells transfected with control- or RECQ1-shRNA plasmid was determined by colony forming assay. (B) Sister chromatid exchanges were assayed in BrdU labeled, giemsa-stained chromosome spreads from control- or RECQ1-siRNA transfected HeLa cells. See ref. .
Figure 2
RECQ1 crystal structure. (A) RECQ1 dimer. Two molecules of RECQ1 in the crystal structure (Protein Database Code 2V1X). A Mg2+-ADP molecule (space-filling model) is bound in the cleft between the two RecA-like domains (colored red and blue). The Zn2+-binding and winged-helix (WH) domains are marked in yellow and green, respectively. The polypeptide chain of the second monomer is shown in light blue, with the regions involved in dimer interaction marked in purple. (B) RECQ1-RecQ overlay. The structure of RECQ1 (colored as in the previous image) aligned with that of E. coli RecQ (pale colors), maximizing the overlap of the RecA-like domains. While the RecA domains and Zn2+-binding domains are well aligned, the WH assumes very different orientations in the two protein structures.
Figure 3
Quelling in Neurospora with an emphasis on potential roles of QDE-3 (RECQ1) homolog with RPA in the pathway. QDE-3: RPA complex may serve in several functions: (1) to resolve secondary structure that forms during replication of tandem repeats; (2) to facilitate transcription of transgenic locus; (3) to recruit QDE-1 to nascent transgenic RNA.
Figure 4
RECQ1 preserves genomic integrity through its proposed role in homologous recombinational repair. See text for details.
References
- Sharma S, Sommers JA, Choudhary S, Faulkner JK, Cui S, Andreoli L, Muzzolini L, Vindigni A, Brosh RM., Jr Biochemical analysis of the DNA unwinding and strand annealing activities catalyzed by human RECQ1. J Biol Chem. 2005;280:28084–272. - PubMed
- Doherty KM, Sharma S, Uzdilla LA, Wilson TM, Cui S, Vindigni A, Brosh RM., Jr RECQ1 helicase interacts with human mismatch repair factors that regulate genetic recombination. J Biol Chem. 2005;280:28085–94. - PubMed
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