CHK2 kinase in the DNA damage response and beyond

Abstract

The serine/threonine kinase CHK2 is a key component of the DNA damage response. In human cells, following genotoxic stress, CHK2 is activated and phosphorylates >20 proteins to induce the appropriate cellular response, which, depending on the extent of damage, the cell type, and other factors, could be cell cycle checkpoint activation, induction of apoptosis or senescence, DNA repair, or tolerance of the damage. Recently, CHK2 has also been found to have cellular functions independent of the presence of nuclear DNA lesions. In particular, CHK2 participates in several molecular processes involved in DNA structure modification and cell cycle progression. In this review, we discuss the activity of CHK2 in response to DNA damage and in the maintenance of the biological functions in unstressed cells. These activities are also considered in relation to a possible role of CHK2 in tumorigenesis and, as a consequence, as a target of cancer therapy.

Keywords: DNA damage; apoptosis; checkpoints; genomic stability.

Figure 1

The DNA damage response and CHK2 functions in human cells. (A) When a lesion is detected, the DNA damage response promotes the appropriate cellular reaction that could be senescence, checkpoint activation, DNA repair, apoptosis, or tolerance of the damage. (B) Overview of common DDR and CHK2 activities related to DNA structure and cell cycle progression.

Figure 2

CHK2 activation and inactivation. (A) CHK2 protein primary structure. (B) After DNA damage, CHK2 monomers are phosphorylated in the SQ/TQ rich region, dimerize, and become active upon autophosphorylation. Successively they dissociate into active monomers. (C) CHK2 inactivation is achieved by degradation, dephosphorylation, and inactivating phosphorylations.

Figure 3

Multiple roles of CHK2 in nuclear DNA damage response. (A) CHK2 in the repair of damaged DNA. CHK2 phosphorylates BRCA1 and BRCA2 to regulate HDR and NHEJ, and phosphorylates FoxM1 to promote FoxM1 accumulation and subsequently BER. N,M,R is the Nbs1/Mre11/Rad50 complex. (B) CHK2 in cell cycle checkpoint activation upon DNA damage. CHK2 phosphorylates p53, Cdc25A, Lats2, and Rb to promote G1/S arrest and phosphorylates p53, Cdc25C, Che-1, Strap, and TTK to induce G2/M checkpoint activation. (C) CHK2 in apoptosis. Upon DNA damage, CHK2 phosphorylates p53 and MdmX to promote p53 accumulation and p53-dependent apoptosis. CHK2 targets E2F1 to induce both p53-dependent and independent apoptosis, and phosphorylates HuR to modulate apoptosis and survival. (D) CHK2 in senescence. CHK2 regulates senescence by targeting TRF2 and possibly acting on p53, p21, and IL-6 and IL-8.

Figure 4

Molecular events that allow CHK2 to sense and respond to different levels of DNA damage.

Figure 5

Functional CHK2 interactors on specialized structures during mitotic phases.

Figure 6

CHK2 in viral infection. Viruses can alter cell cycle control and DNA replication, with important consequences on the DDR.