RECQL4 in genomic instability and aging

Abstract

Helicases are ubiquitous proteins that unwind DNA and participate in DNA metabolism including replication, repair, transcription, and chromatin organization. The highly conserved RecQ helicase family proteins are important in these transactions and have been termed the guardians of the genome. Humans have five members of this family: WRN, BLM, RECQL4, RECQL1, and RECQL5. The first three of are associated with premature aging and cancer prone syndromes, but the latter two proteins have not yet been implicated in any human disease. Although WRN and BLM have been fairly well characterized, RECQL4 has only recently been intensively investigated. The sum of this work to date has shown that RECQL4 has helicase activity and localizes to telomeres and mitochondria. In addition, new protein partners are emerging, implicating RECQL4 in novel processes. Here, we describe these recent findings which place RECQL4 at the crossroads of genomic instability and aging processes.

Figure 1

Structural organization of human RecQ helicases. All the RecQ helicase members possess a highly conserved helicase domain (yellow). The nuclear localization signal (purple) is present at the C-terminus in most of the family members, except in RECQL4 which has two nuclear targeting sequences (NTS1and NTS2) that are present at the N-terminus. The RQC (pink) and helicase and RNase C-terminal (HRDC) domain (black) are present at the C-terminus of helicase domain except for in RECQL4. The WRN protein is unique among human RecQ helicase members in having an exonuclease domain (green) at the N-terminus. The N-terminus of RECQL4 show sequence similarity with the Sld2 protein in yeast that is important for DNA replication and cell viability. A putative mitochondrial targeting sequence is present at the N-terminus of RECQL4 (light blue).

Figure 2

RECQL4 has a narrower substrate range than other RecQ helicases. The RECQL4 helicase can unwind forked duplexes (A), D-loops (B), and bubble (C) structures but not duplex DNA (D), Holliday junctions (E), or G-quadruplex structures (F). However, the unwinding activity from the N-terminal domain can utilize duplex DNA substrates.

Figure 3

Cellular localization and stress responses surrounding RECQL4. Under normal circumstances, RECQL4 can be found in the nucleoplasm and at telomeres, where it participates in DNA maintenance. Without stress, RECQL4 interacts with p53 and they shuttle between the nucleus and mitochondria. After stress, p53 and RECQL4 re-localize to the nucleus where p53 coordinates the DNA damage response including down-regulating RECQL4 expression. In both the nucleus and mitochondria, RECQL4 can localize to DNA damage and participate in modulating DNA maintenance processes.