Spirulina and DNA Damage Response: ATM/ATR, Checkpoint Kinases, and DSB Repair

DNA Damage Sensors: ATM and ATR

Ataxia telangiectasia mutated (ATM) responds primarily to DNA double-strand breaks (DSBs): the MRN complex (MRE11-RAD50-NBS1) binds DSBs and recruits ATM, which autophosphorylates at Ser1981 and activates as a homodimer to monomer transition. ATM phosphorylates H2AX at Ser139 (gammaH2AX, DSB marker), MDM2 Ser395 (stabilising p53), CHK2 Thr68, and BRCA1 Ser1524. ATR (ATM and Rad3-related) responds to single-strand DNA/RPA coating (stalled replication forks, UV lesions) via ATRIP-RPA recognition, TopBP1/ETAA1 activation, and CHK1 Ser317/345 phosphorylation. Oxidative DNA lesions (8-OHdG, thymine glycols, abasic sites) trigger SSB signalling and, if two SSBs are proximal, DSBs, activating ATM.

Spirulina Reduction of Oxidative DNA Damage

Nrf2-driven induction of OGG1 (8-oxoguanine DNA glycosylase), APEX1 (APE1 apurinic/apyrimidinic endonuclease), and NEIL1/2 base excision repair (BER) enzymes reduces the steady-state level of oxidative DNA lesions. Multiple animal studies (cyclophosphamide model, gamma-irradiation, CCl4 hepatotoxicity) show spirulina significantly reduces gammaH2AX foci and micronucleus frequency, consistent with both reduced DNA damage induction (antioxidant protection) and enhanced BER capacity (Nrf2-driven enzyme induction). The comet assay (alkaline single-cell gel electrophoresis) demonstrates reduced strand breaks in peripheral blood lymphocytes of animals supplemented with spirulina.

CHK1 and CHK2: Cell Cycle Checkpoint Kinases

CHK1 (S/G2 checkpoint, phosphorylates CDC25A Ser123 for proteasomal degradation and CDC25C Ser216 for 14-3-3 cytoplasmic sequestration, preventing CDK1 activation) and CHK2 (G1/S checkpoint, phosphorylates p53 Ser20 and MDM2) together enforce cell cycle arrest upon DNA damage, providing time for repair. CHK1 is also active in unperturbed S phase to slow replication at fragile sites. Spirulina's reduction of replication stress (via reduced oxidative dNTP pool damage, OGG1 BER preserving template integrity) reduces basal CHK1 activation, potentially supporting genomic stability in proliferating cells.

Homologous Recombination: BRCA1, PALB2, RAD51

DSB repair by homologous recombination (HR) requires: (1) resection (MRN-CtIP-EXO1/DNA2 generating 3-prime ssDNA overhang); (2) RPA coating; (3) RAD51 nucleofilament formation (loaded by BRCA2/PALB2/BRCA1 complex, displacing RPA); (4) strand invasion into homologous template; (5) branch migration and Holliday junction resolution. BRCA1 and RAD51 expression are cell-cycle regulated (S/G2 phase). Nrf2 activation upregulates several HR genes including XRCC2 and RAD51D. Spirulina's Nrf2 activation supports HR capacity, complementing its reduction of initial DSB formation from oxidative stress.

NHEJ: Ku70/Ku80, DNA-PKcs, and XRCC4

Non-homologous end joining (NHEJ), active in all cell cycle phases, involves: Ku70/Ku80 heterodimer binding to DSB ends, recruiting DNA-PKcs (autophosphorylation Ser2056), Artemis nuclease (end processing), XRCC4-LigIV-XLF (ligation), and PAXX. NHEJ is intrinsically error-prone (microhomology-mediated end joining, deletions), but essential for lymphocyte V(D)J recombination and immunoglobulin class switch. DNA-PKcs is also activated by oxidative stress via reactive oxygen species independently of DSBs. Nrf2 suppression of ROS reduces spurious DNA-PKcs activation, preventing unnecessary NHEJ errors.

p53 Stabilisation and Spirulina

p53 (TP53) is stabilised by ATM-mediated MDM2 phosphorylation (Ser395, reducing MDM2-p53 interaction) and by direct p53 phosphorylation (Ser15/Ser20 by ATM/CHK2, reducing MDM2 binding). Stable p53 transactivates: CDKN1A (p21, CDK inhibitor), GADD45A (G2/M arrest), BAX/PUMA/NOXA (apoptosis in irreparable damage), and TIGAR (PFKFB3 homologue, redirecting glycolytic intermediates to pentose phosphate pathway for NADPH/ribose). Spirulina maintains p53 function by reducing oxidative DNA damage that would otherwise saturate the DDR, while AMPK-mediated energy sensing cooperates with p53 for metabolic adaptation to genotoxic stress.