ATM, DNA-PKcs and ATR: shaping development through the regulation of the DNA damage responses

Demis Menolfi; Shan Zha

doi:10.1007/s42764-019-00003-9

Genome Instability & Disease ›› 2019, Vol. 1 ›› Issue (2) : 47 -68. DOI: 10.1007/s42764-019-00003-9

Review Article

ATM, DNA-PKcs and ATR: shaping development through the regulation of the DNA damage responses

Demis Menolfi ¹
, Shan Zha ¹^,²^,³^,^b

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Abstract

Genomic integrity is critical for normal development, healthy aging and suppressing oncogenic transformation. The DNA damage response (DDR) is a complex network that is activated by DNA structural changes to preserve genome integrity. Situated at the apex of the mammalian DDR are three PI3-kinase-related protein kinases—ATM, DNA-PKcs and ATR. They are activated by different DNA lesions via direct binding to their unique sensor protein complexes (MRE11-RAD50-NBS1 for ATM, Ku70-Ku80/86 for DNA-PKcs and ATRIP-RPA for ATR) and phosphorylate a large number of partially overlapping substrates, including themselves and each other to promote DNA repair and regulate cell cycle checkpoints and tissue homeostasis. This review focuses on mouse models with deletion and point mutations of ATM, DNA-PKcs and ATR, and discusses how their activation mechanism and their kinase activity contribute to their unique, yet interactive roles in DNA repair in general and during tissue-specific development processes and how their deficiency leads to specific physiological and pathophysiological consequences.

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Demis Menolfi, Shan Zha. ATM, DNA-PKcs and ATR: shaping development through the regulation of the DNA damage responses. Genome Instability & Disease, 2019, 1(2): 47-68 DOI:10.1007/s42764-019-00003-9