Trends in Genetics
ReviewRECQL4 in genomic instability and aging
Section snippets
The Human RecQ helicases
DNA helicases are important ubiquitous enzymes that participate in DNA metabolism and affect genome stability. Helicases hydrolyze ATP to translocate along DNA, separating the two DNA strands and dislodging proteins in their path. Bacteria and yeast express a single RecQ helicase whereas humans express five: BLM, WRN, RECQL1, RECQL4, and RECQL5. All these proteins share the core motifs of the RecQ helicase family, but outside this homology the proteins vary significantly (Figure 1). Loss of
Structural and functional uniqueness of RECQL4
Human RECQL4 is a 1208 amino acid (aa) protein containing a highly conserved 3′ to 5′ helicase domain in the center of the protein. RecQ helicase family members typically have the conserved helicase motifs, a RecQ conserved domain (RQC), and the helicase and RNase D conserved domain (HRDC), but curiously RECQL4 lacks the latter two (Figure 1).
Both the N- and C-terminal regions of RECQL4 contain distinct sequences from the other RecQ family helicases. The N-terminal region of RECQL4 is a
RECQL4 protein interactions
Currently, more than 10 proteins have been shown to associate with RECQL4 in vivo (Table 1), implicating the protein not only in DNA-related pathways but also in post-translational modifications, telomere maintenance, and mitochondrial DNA (mtDNA) maintenance. Similarly to other RecQ proteins, multiple lines of evidence support a role for RECQL4 in DNA replication. xRECQL4, which is essential for DNA replication in Xenopus egg extracts [25], is part of the replication initiation complex and
Aging mechanisms
Recently, several discoveries have demonstrated functional roles for RECQL4 in three major mechanisms associated with aging and cellular senescence: oxidative DNA damage repair, telomere maintenance, and mitochondrial dysfunction (Figure 3). Oxidative damage, caused by endogenous cellular metabolism or exogenous sources, disrupts normal replication and transcription and leads to genomic instability and cellular senescence. BER is the primary mechanism to repair oxidative lesions and prevent
Concluding remarks
A future challenge is to understand the biological function of RECQL4 in both compartments, as well as whether and how it could function as a signaling molecule between these compartments. RECQL4 is the only RecQ helicase known to function in mitochondria, and a greater understanding of its function in this compartment should be a focus of future research. This is challenging in general because of the low abundance of DNA metabolic proteins in the mitochondria and particularly by the fact that
Acknowledgments
We would like to thank Martin Borch Jensen and Dr Venkateswarlu Popuri for critically reading the manuscript. We would like to thank Thomas Wynn for his artwork. This research was supported entirely by the Intramural Research Program of the National Institutes of Health, National Institute on Aging, AG000726–20.
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