RECQL4
ATP-dependent DNA helicase Q4 (EC 3.6.4.12) (DNA helicase, RecQ-like type 4) (RecQ4) (RTS) (RecQ protein-like 4) [RECQ4]
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Rothmund-Thomson Syndrome (RTS) is a rare autosomal recessive disease which manifests several clinical features of accelerated aging. These findings include atrophic skin and pigment changes, alopecia, osteopenia, cataracts, and an increased incidence of cancer for patients carrying RECQL4 germline mutations. Mutations in RECQL4 are responsible for the majority of cases of RTS. RECQL4 belongs to RECQ DNA helicase family which has been shown to participate in many aspects of DNA metabolism. In the past several years, accumulated evidence indicates that RECQL4 is important not only in cancer development but also in the aging process. In this review, based on recent research data, we summarize the common aging findings in RTS patients and propose possible mechanisms to explain the aging features in these patients.
MeSH Terms
- Aging
- Humans
- Mutation
- RecQ Helicases
- Rothmund-Thomson Syndrome
- Symptom Assessment
Keywords
- DNA damage repair
- Mitochondria
- RECQL4
- Rothmund-Thomson syndrome
- Senescence
- Telomere
Genomic instability is a hallmark of cancer and aging. Premature aging (progeroid) syndromes are often caused by mutations in genes whose function is to ensure genomic integrity. The RecQ family of DNA helicases is highly conserved and plays crucial roles as genome caretakers. In humans, mutations in three RecQ genes - BLM, WRN, and RECQL4 - give rise to Bloom's syndrome (BS), Werner syndrome (WS), and Rothmund-Thomson syndrome (RTS), respectively. WS is a prototypic premature aging disorder; however, the clinical features present in BS and RTS do not indicate accelerated aging. The BLM helicase has pivotal functions at the crossroads of DNA replication, recombination, and repair. BS cells exhibit a characteristic form of genomic instability that includes excessive homologous recombination. The excessive homologous recombination drives the development in BS of the many types of cancers that affect persons in the normal population. Replication delay and slower cell turnover rates have been proposed to explain many features of BS, such as short stature. More recently, aberrant transcriptional regulation of growth and survival genes has been proposed as a hypothesis to explain features of BS.
MeSH Terms
- Aging
- Aging, Premature
- Bloom Syndrome
- DNA Helicases
- DNA Replication
- Genomic Instability
- Humans
- Mutation
- RecQ Helicases
- Werner Syndrome
- Werner Syndrome Helicase
Keywords
- Aging
- BLM
- Bloom’s syndrome
- Cancer susceptibility
- Genomic instability
- RecQ helicases
Cellular senescence refers to irreversible growth arrest of primary eukaryotic cells, a process thought to contribute to aging-related degeneration and disease. Deficiency of RecQ helicase RECQL4 leads to Rothmund-Thomson syndrome (RTS), and we have investigated whether senescence is involved using cellular approaches and a mouse model. We first systematically investigated whether depletion of RECQL4 and the other four human RecQ helicases, BLM, WRN, RECQL1 and RECQL5, impacts the proliferative potential of human primary fibroblasts. BLM-, WRN- and RECQL4-depleted cells display increased staining of senescence-associated β-galactosidase (SA-β-gal), higher expression of p16(INK4a) or/and p21(WAF1) and accumulated persistent DNA damage foci. These features were less frequent in RECQL1- and RECQL5-depleted cells. We have mapped the region in RECQL4 that prevents cellular senescence to its N-terminal region and helicase domain. We further investigated senescence features in an RTS mouse model, Recql4-deficient mice (Recql4(HD)). Tail fibroblasts from Recql4(HD) showed increased SA-β-gal staining and increased DNA damage foci. We also identified sparser tail hair and fewer blood cells in Recql4(HD) mice accompanied with increased senescence in tail hair follicles and in bone marrow cells. In conclusion, dysfunction of RECQL4 increases DNA damage and triggers premature senescence in both human and mouse cells, which may contribute to symptoms in RTS patients.
MeSH Terms
- Age Factors
- Aging
- Animals
- Bone Marrow Cells
- Cell Proliferation
- Cells, Cultured
- Cellular Senescence
- Cyclin-Dependent Kinase Inhibitor p16
- Cyclin-Dependent Kinase Inhibitor p21
- DNA Damage
- Disease Models, Animal
- Exodeoxyribonucleases
- Fibroblasts
- Genetic Predisposition to Disease
- Hair Follicle
- Humans
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Phenotype
- Protein Structure, Tertiary
- RNA Interference
- RecQ Helicases
- Rothmund-Thomson Syndrome
- Transfection
- Werner Syndrome Helicase