Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest and activation of DNA repair in response to the presence of DNA damage or unreplicated DNA (PubMed:10859163, PubMed:10859164, PubMed:15261141). May also negatively regulate cell cycle progression during unperturbed cell cycles (PubMed:10859163, PubMed:10859164, PubMed:15261141). This regulation is achieved by a number of mechanisms that together help to preserve the integrity of the genome (PubMed:10859163, PubMed:10859164, PubMed:15261141). Recognizes the substrate consensus sequence [R-X-X-S/T] (PubMed:10859163, PubMed:10859164, PubMed:15261141). Binds to and phosphorylates CDC25A, CDC25B and CDC25C. Phosphorylation of CDC25A at 'Ser-178' and 'Thr-507' and phosphorylation of CDC25C at 'Ser-216' creates binding sites for 14-3-3 proteins which inhibit CDC25A and CDC25C. Phosphorylation of CDC25A at 'Ser-76', 'Ser-124', 'Ser-178', 'Ser-279' and 'Ser-293' promotes proteolysis of CDC25A. Phosphorylation of CDC25A at 'Ser-76' primes the protein for subsequent phosphorylation at 'Ser-79', 'Ser-82' and 'Ser-88' by NEK11, which is required for polyubiquitination and degradation of CDCD25A. Inhibition of CDC25 leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression. Also phosphorylates NEK6. Binds to and phosphorylates RAD51 at 'Thr-309', which promotes the release of RAD51 from BRCA2 and enhances the association of RAD51 with chromatin, thereby promoting DNA repair by homologous recombination. Phosphorylates multiple sites within the C-terminus of TP53, which promotes activation of TP53 by acetylation and promotes cell cycle arrest and suppression of cellular proliferation. Also promotes repair of DNA cross-links through phosphorylation of FANCE. Binds to and phosphorylates TLK1 at 'Ser-743', which prevents the TLK1-dependent phosphorylation of the chromatin assembly factor ASF1A. This may enhance chromatin assembly both in the presence or absence of DNA damage. May also play a role in replication fork maintenance through regulation of PCNA (By similarity). May regulate the transcription of genes that regulate cell-cycle progression through the phosphorylation of histones. Phosphorylates histone H3.1 (to form H3T11ph), which leads to epigenetic inhibition of a subset of genes (PubMed:18243098). May also phosphorylate RB1 to promote its interaction with the E2F family of transcription factors and subsequent cell cycle arrest. Phosphorylates SPRTN, promoting SPRTN recruitment to chromatin (By similarity). Reduces replication stress and activates the G2/M checkpoint, by phosphorylating and inactivating PABIR1/FAM122A and promoting the serine/threonine-protein phosphatase 2A-mediated dephosphorylation and stabilization of WEE1 levels and activity (By similarity). ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-[protein] ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-threonyl-[protein] Activated through phosphorylation predominantly by ATR but also by ATM in response to DNA damage or inhibition of DNA replication. Activation is modulated by several mediators including CLSPN, BRCA1 and FEM1B. Proteolytic cleavage at the C-terminus by SPRTN during normal DNA replication activates the protein kinase activity. Interacts (phosphorylated by ATR) with RAD51 (By similarity). Interacts with and phosphorylates CLSPN, an adapter protein that regulates the ATR-dependent phosphorylation of CHEK1 (By similarity). Interacts with BRCA1 (By similarity). Interacts with and phosphorylates CDC25A, CDC25B and CDC25C (By similarity). Interacts with FBXO6, which regulates CHEK1 (By similarity). Interacts with PPM1D, which regulates CHEK1 through dephosphorylation (By similarity). Interacts with TIMELESS; DNA damage-dependent (PubMed:23418588). Interacts with FEM1B; activates CHEK1 in response to stress (By similarity). Interacts with TLK1 (By similarity). Interacts with XPO1 and YWHAZ (By similarity). Interacts with CDK5RAP3; antagonizes CHEK1 (By similarity). Nuclear export is mediated at least in part by XPO1/CRM1. Also localizes to the centrosome specifically during interphase, where it may protect centrosomal CDC2 kinase from inappropriate activation by cytoplasmic CDC25B. Proteolytic cleavage at the C-terminus by SPRTN promotes removal from chromatin. Found in all adult tissues tested. Elevated expression in testis, lung and spleen. 15.5 day old embryos show ubiquitous expression with strong expression in brain, liver, kidney, pancreas, intestine, thymus and lung. In the testis, present in cells undergoing meiosis I. Not detected in peripheral cells in seminiferous tubules that are undergoing pre-meiotic DNA synthesis or in late condensing or mature sperm. The autoinhibitory region (AIR) inhibits the activity of the kinase domain. Phosphorylated by ATR in a RAD17-dependent manner in response to ultraviolet irradiation and inhibition of DNA replication. Phosphorylated by ATM in response to ionizing irradiation. ATM and ATR can both phosphorylate Ser-317 and Ser-345 and this results in enhanced kinase activity. Phosphorylation at Ser-345 induces a change in the conformation of the protein, activates the kinase activity and is a prerequisite for interaction with FBXO6 and subsequent ubiquitination at Lys-436. Phosphorylation at Ser-345 also increases binding to 14-3-3 proteins and promotes nuclear retention. Conversely, dephosphorylation at Ser-345 by PPM1D may contribute to exit from checkpoint mediated cell cycle arrest. Phosphorylation at Ser-280 by AKT1/PKB, may promote mono and/or diubiquitination. Also phosphorylated at undefined residues during mitotic arrest, resulting in decreased activity. Ubiquitinated (PubMed:15710331). Mono or diubiquitination promotes nuclear exclusion (PubMed:15710331). The activated form (phosphorylated on Ser-345) is polyubiquitinated at Lys-436 by some SCF-type E3 ubiquitin ligase complex containing FBXO6 promoting its degradation (By similarity). Ubiquitination and degradation are required to terminate the checkpoint and ensure that activated CHEK1 does not accumulate as cells progress through S phase, when replication forks encounter transient impediments during normal DNA replication. 'Lys-63'-mediated ubiquitination by TRAF4 at Lys-132 activates cell cycle arrest and activation of DNA repair (By similarity). Proteolytically cleaved at the C-terminus by SPRTN during normal DNA replication, thereby promoting CHEK1 removal from chromatin and activating the protein kinase activity. Mice die of apoptosis at the blastocyst stage. Haploinsufficient for the suppression of genomic instability and tumor progression. 3 initiator methionines can be considered. If this isoform were to start at the first ATG, it would produce a 28 amino acid-long peptide, sharing the first 22 amino acids with the canonical sequence (isoform 1) and differing in the last 6 residues (VQLAVN -> ARHRDA). An initiation at this site could target the mRNA to nonsense-mediated mRNA decay and, in this case, the peptide would be produced at very low levels. The second possible translation initiation site would lead to the synthesis of the sequence shown in this entry as isoform 2. However, the Kozak sequence for this site is not optimal. Finally the third potential initiator methionine corresponds to position 167 in isoform 1 and would lead to the synthesis of a 310 amino acid-long protein identical to isoform 1 residues 167 through 476. Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. NIM1 subfamily. Extended N-terminus.