CDK2 phosphorylation of Werner protein (WRN) contributes to WRN’s DNA double‐strand break repair pathway choice

Lee, Jong-Hyuk; Shamanna, Raghavendra A.; Kulikowicz, Tomasz; Fakouri, Nima Borhan; Kim, Edward W.; Christiansen, Louise S.; Croteau, Deborah L.; Bohr, Vilhelm A.

doi:10.1111/acel.13484

Cited by 10 publications

(5 citation statements)

References 61 publications

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“…Extensive biochemical studies of the pathologies of WS have been focused mainly on DNA damage 1 , 2 , genomic instability 2 , and mitochondrial homeostasis 9 . Patients with WS or those with cells missing WRN are highly susceptible to DNA-damaging agents, highlighting the critical involvement of WRN in DNA repair 10 . However, the mechanism behind the short stature in WS patients remains elusive.…”

Section: Introductionmentioning

confidence: 99%

WRN promotes bone development and growth by unwinding SHOX-G-quadruplexes via its helicase activity in Werner Syndrome

et al. 2022

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Werner Syndrome (WS) is an autosomal recessive disorder characterized by premature aging due to mutations of the WRN gene. A classical sign in WS patients is short stature, but the underlying mechanisms are not well understood. Here we report that WRN is indispensable for chondrogenesis, which is the engine driving the elongation of bones and determines height. Zebrafish lacking wrn exhibit impairment of bone growth and have shorter body stature. We pinpoint the function of WRN to its helicase domain. We identify short-stature homeobox (SHOX) as a crucial and direct target of WRN and find that the WRN helicase core regulates the transcriptional expression of SHOX via unwinding G-quadruplexes. Consistent with this, shox −/− zebrafish exhibit impaired bone growth, while genetic overexpression of SHOX or shox expression rescues the bone developmental deficiency induced in WRN / wrn -null mutants both in vitro and in vivo. Collectively, we have identified a previously unknown function of WRN in regulating bone development and growth through the transcriptional regulation of SHOX via the WRN helicase domain, thus illuminating a possible approach for new therapeutic strategies.

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Section: Introductionmentioning

confidence: 99%

WRN promotes bone development and growth by unwinding SHOX-G-quadruplexes via its helicase activity in Werner Syndrome

et al. 2022

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“…Cyclin-dependent kinase 2 (CDK2) is a critical cell cycle regulator of G1/S [1][2][3][4][5]. CDK2 is also involved during DDR, HR, signal transduction, apoptosis, and DNA and RNA metabolism in cells [6][7][8][9][10]13]. Here, we comprehensively evaluated CDK2 in BC.…”

Section: Discussionmentioning

confidence: 99%

“…Besides playing a critical role in cell cycle progression, CDK2 is also involved in the DNA damage signalling response (DDR) in cells [6][7][8][9][10]. CDK2 has been shown to be involved during the homologous recombination (HR) pathway via activation of MRN-CtIP-BRCA1, which is essential for the repair of DNA double-strand breaks [11].…”

Section: Introductionmentioning

confidence: 99%

Clinicopathological Significance of Cyclin-Dependent Kinase 2 (CDK2) in Ductal Carcinoma In Situ and Early-Stage Invasive Breast Cancers

Lashen,

Alqahtani,

Shoqafi

et al. 2024

IJMS

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Cyclin-dependent kinase 2 (CDK2) is a key cell cycle regulator, with essential roles during G1/S transition. The clinicopathological significance of CDK2 in ductal carcinomas in situ (DCIS) and early-stage invasive breast cancers (BCs) remains largely unknown. Here, we evaluated CDK2’s protein expression in 479 BC samples and 216 DCIS specimens. Analysis of CDK2 transcripts was completed in the METABRIC cohort (n = 1980) and TCGA cohort (n = 1090), respectively. A high nuclear CDK2 protein expression was significantly associated with aggressive phenotypes, including a high tumour grade, lymph vascular invasion, a poor Nottingham prognostic index (all p-values < 0.0001), and shorter survival (p = 0.006), especially in luminal BC (p = 0.009). In p53-mutant BC, high nuclear CDK2 remained linked with worse survival (p = 0.01). In DCIS, high nuclear/low cytoplasmic co-expression showed significant association with a high tumour grade (p = 0.043), triple-negative and HER2-enriched molecular subtypes (p = 0.01), Comedo necrosis (p = 0.024), negative ER status (p = 0.004), negative PR status (p < 0.0001), and a high proliferation index (p < 0.0001). Tumours with high CDK2 transcripts were more likely to have higher expressions of genes involved in the cell cycle, homologous recombination, and p53 signaling. We provide compelling evidence that high CDK2 is a feature of aggressive breast cancers. The clinical evaluation of CDK2 inhibitors in early-stage BC patients will have a clinical impact.

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“…Although the classical function of the pathogenic genes has been well characterized, their novel roles in regulating genome stability are still to be investigated. A recent paper has shown that Werner protein (WRN) participates in the regulation of HR/NHEJ pathway choice in a CDK2-dependent manner (Lee et al, 2021). Moreover, in HGPS cells, the NER factor XPA mysteriously colocalizes with γ-H2AX, the marker of DSB (Liu et al, 2008), and the BER capacity also decreases, attributing to the reduced expression or activity of several BER factors in HGPS cells (Maynard et al, 2019).…”

Section: Age-associated Alterations In Genome Stability: Mechanisms A...mentioning

confidence: 99%

The landscape of aging

Cai

Song

et al. 2022

Sci. China Life Sci.

159

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Aging is characterized by a progressive deterioration of physiological integrity, leading to impaired functional ability and ultimately increased susceptibility to death. It is a major risk factor for chronic human diseases, including cardiovascular disease, diabetes, neurological degeneration, and cancer. Therefore, the growing emphasis on “healthy aging” raises a series of important questions in life and social sciences. In recent years, there has been unprecedented progress in aging research, particularly the discovery that the rate of aging is at least partly controlled by evolutionarily conserved genetic pathways and biological processes. In an attempt to bring full-fledged understanding to both the aging process and age-associated diseases, we review the descriptive, conceptual, and interventive aspects of the landscape of aging composed of a number of layers at the cellular, tissue, organ, organ system, and organismal levels.

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CDK2 phosphorylation of Werner protein (WRN) contributes to WRN’s DNA double‐strand break repair pathway choice

Cited by 10 publications

References 61 publications

WRN promotes bone development and growth by unwinding SHOX-G-quadruplexes via its helicase activity in Werner Syndrome

WRN promotes bone development and growth by unwinding SHOX-G-quadruplexes via its helicase activity in Werner Syndrome

Clinicopathological Significance of Cyclin-Dependent Kinase 2 (CDK2) in Ductal Carcinoma In Situ and Early-Stage Invasive Breast Cancers

The landscape of aging

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