TINF2 is a major susceptibility gene in Danish patients with multiple primary melanoma

Jensen, Marlene Richter; Jelsig, Anne Marie; Gerdes, Anne–Marie; Hølmich, Lisbet Rosenkrantz; Kainu, Kati; Lorentzen, Henrik; Hansen, Michael Sejer; Bak, Mads; Johansson, Peter; Hayward, Nicholas K.; Hansen, Thomas van Overeem; Wadt, Karin

doi:10.1016/j.xhgg.2023.100225

Cited by 2 publications

References 55 publications

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Cell Senescence and the Genetics of Melanoma Development

Constantinou,

Bennett

2024

Genes Chromosomes & Cancer

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Cutaneous malignant melanoma is an aggressive skin cancer with an approximate lifetime risk of 1 in 38 in the UK. While exposure to ultraviolet radiation is a key environmental risk factor for melanoma, up to ~10% of patients report a family history of melanoma, and ~1% have a strong family history. The understanding of causal mutations in melanoma has been critical to the development of novel targeted therapies that have contributed to improved outcomes for late‐stage patients. Here, we review current knowledge of the genes affected by familial melanoma mutations and their partial overlap with driver genes commonly mutated in sporadic melanoma development. One theme linking a set of susceptibility loci/genes is the regulation of skin pigmentation and suntanning. The largest functional set of susceptibility variants, typically with high penetrance, includes CDKN2A, RB1, and telomerase reverse transcriptase (TERT) mutations, associated with attenuation of cell senescence. We discuss the mechanisms of action of these gene sets in the biology and progression of nevi and melanoma.

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Cell Senescence and the Genetics of Melanoma Development

Constantinou,

Bennett

2024

Genes Chromosomes & Cancer

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Replicative senescence is ATM driven, reversible, and accelerated by hyperactivation of ATM at normoxia

Stuart,

de Lange

2024

Preprint

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Programmed telomere shortening limits tumorigenesis through the induction of replicative senescence. Here we address three long-standing questions concerning senescence. First, we show that the ATM kinase is solely responsible for the induction of replicative senescence. Senescence was delayed by ATM inhibition (ATMi) or overexpression of TRF2, the shelterin subunit dedicated to ATM repression. In contrast, there was no evidence for ATR signaling contributing to replicative senescence even when ATMi was combined with ATR inhibition. Second, we show ATMi can induce apparently normal cell divisions in a subset of senescent cells, indicating that senescence can be reversed. Third, we show that the extended replicative life span at low (physiological) oxygen is due to diminished ATM activity. At low oxygen, cells show a decreased ATM response to dysfunctional telomeres and genome-wide DSBs compared to 20% oxygen. As this effect could be reversed by NAC, the attenuated response of ATM to critically short telomeres and the resulting extended life span at low oxygen is likely due to ROS-induced formation of cysteine disulfide-bridges that crosslink ATM dimers into a form that is not activated by DSBs. These findings show how primary human cells detect shortened telomeres and reveal the molecular mechanism underlying the telomere tumor suppressor pathway.

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TINF2 is a major susceptibility gene in Danish patients with multiple primary melanoma

Cited by 2 publications

References 55 publications

Cell Senescence and the Genetics of Melanoma Development

Cell Senescence and the Genetics of Melanoma Development

Replicative senescence is ATM driven, reversible, and accelerated by hyperactivation of ATM at normoxia

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