SDE2 integrates into the TIMELESS-TIPIN complex to protect stalled replication forks
| Autor: | Ping Ping Zeng, Jung-Eun Yeo, Hyungjin Kim, Sunyoung Hwang, Jennifer J. Park, Julie Rageul, Alexandra S. Weinheimer, Jihyeon Yang, Natalie Lo, Orlando D. Schärer, Eun-A Lee |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
DNA Replication DNA Repair DNA repair DNA damage Timeless Science General Physics and Astronomy Cell Cycle Proteins Biology DNA damage response General Biochemistry Genetics and Molecular Biology Article Genomic Instability 03 medical and health sciences 0302 clinical medicine Replication fork protection complex Protein Domains Humans DNA damage checkpoints Phosphorylation lcsh:Science Genome stability MRE11 Homologue Protein Multidisciplinary Replication stress DNA damage and repair DNA replication Intracellular Signaling Peptides and Proteins Nuclear Proteins General Chemistry Replication (computing) Cell biology DNA-Binding Proteins 030104 developmental biology HEK293 Cells Chromosome Structures Gene Expression Regulation 030220 oncology & carcinogenesis Gene Knockdown Techniques Checkpoint Kinase 1 Replisome Fork (file system) lcsh:Q DNA Damage |
| Zdroj: | Nature Communications Nature Communications, Vol 11, Iss 1, Pp 1-16 (2020) |
| ISSN: | 2041-1723 |
| Popis: | Protecting replication fork integrity during DNA replication is essential for maintaining genome stability. Here, we report that SDE2, a PCNA-associated protein, plays a key role in maintaining active replication and counteracting replication stress by regulating the replication fork protection complex (FPC). SDE2 directly interacts with the FPC component TIMELESS (TIM) and enhances its stability, thereby aiding TIM localization to replication forks and the coordination of replisome progression. Like TIM deficiency, knockdown of SDE2 leads to impaired fork progression and stalled fork recovery, along with a failure to activate CHK1 phosphorylation. Moreover, loss of SDE2 or TIM results in an excessive MRE11-dependent degradation of reversed forks. Together, our study uncovers an essential role for SDE2 in maintaining genomic integrity by stabilizing the FPC and describes a new role for TIM in protecting stalled replication forks. We propose that TIM-mediated fork protection may represent a way to cooperate with BRCA-dependent fork stabilization. The fork protection complex (FPC), including the proteins TIMELESS and TIPIN, stabilizes the replisome to ensure unperturbed fork progression during DNA replication. Here the authors reveal that that SDE2, a PCNA-associated protein, plays an important role in maintaining active replication and protecting stalled forks by regulating the replication fork protection complex (FPC). |
| Databáze: | OpenAIRE |
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