Ultraviolet radiation stress triggers the down-regulation of essential replication factor Mcm10.
We report that upon UV radiation insult, mammalian cells specifically down-regulate Mcm10, a protein essential for the initiation and elongation phases of DNA replication. The levels of a majority of replication factors remain unaffected under this condition, implying that Mcm10 is a key node in the regulation of the replication machinery. High doses of ionizing gamma radiation and exposure to a combination of DNA-damaging chemicals do not decrease Mcm10 protein levels, demonstrating that Mcm10 down-regulation is triggered only by UV-specific damage. The decrease of Mcm10 protein levels is not caused by transcriptional inhibition or cleavage by apoptotic enzymes, but results from degradation by the 26 S proteasome. UV-triggered degradation of Mcm10 requires its linker or C-terminal domain. In addition, Mcm10 down-regulation is not limited to cells from a particular lineage. Therefore, our study reveals a mechanism by which mammalian cells effectively inhibit the replication machinery during stress to prevent it from drifting toward a catastrophic path of genomic instability.
Sharma
Aparna
A
National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India.
Kaur
Manpreet
M
Kar
Ananya
A
Ranade
Sourabh M
SM
Saxena
Sandeep
S
D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division / Q000502:physiology / Q000528:radiation effects; D004249:DNA Damage / Q000502:physiology; D004260:DNA Repair / Q000502:physiology; D004261:DNA Replication / Q000502:physiology* / Q000528:radiation effects*; D004307:Dose-Response Relationship, Radiation; D015536:Down-Regulation / Q000187:drug effects / Q000528:radiation effects; D005720:Gamma Rays; D006367:HeLa Cells; D006801:Humans; D064110:Minichromosome Maintenance Proteins; D012516:Osteosarcoma; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering; D016196:S Phase / Q000502:physiology / Q000528:radiation effects; D013312:Stress, Physiological / Q000502:physiology / Q000528:radiation effects; D014158:Transcription, Genetic / Q000502:physiology; D014466:Ultraviolet Rays
D000903:Antibiotics, Antineoplastic; D018797:Cell Cycle Proteins; C489613:MCM10 protein, human; D034741:RNA, Small Interfering; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D064110:Minichromosome Maintenance Proteins