Inactive Tlk associating with Tak1 increases p38 MAPK activity to prolong the G2 phase

Sci Rep. 2019 Feb 13;9(1):1885. doi: 10.1038/s41598-018-36137-1.

Abstract

To guard genome integrity, response mechanisms coordinately execute the G2/M checkpoint in responding to stress. p38 MAPK is activated to prolong the G2 phase for completion of damage repair. Tlk activity is required for DNA repair, chromosome segregation and G2 recovery. However, the involvement of Tlk in G2 recovery differs from previous findings that Tlk overexpression delays the G2/M transition. To clarify this difference, genetic interaction experiments were performed using the second mitotic wave as model system. The results indicate that Tlk overexpression prolongs the G2 phase through p38 MAPK activation, independent of Tlk kinase activity. The results of co-immunoprecipitation, database search and RNAi screening suggest that eEF1α1 and Hsc70-5 links Tlk to Tak1. Reduced gene activities of Tlk, Hsc70-5, eEF1α1 and/or Tak1 couldn't prolong the G2 phase induced by heat shock, indicating that these proteins work together to elevate p38 MAPK activity. In contrast, a high level of wild type Tlk decreases phosphorylated p38 MAPK levels. Thus, the difference is explained by a dual function of Tlk. When under stress, inactive Tlk increases p38 MAPK activity to prolong the G2 phase, and then activated Tlk modulates activities of p38 MAPK and Asf1 to promote G2 recovery afterwards.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified / metabolism
  • Drosophila / metabolism
  • Drosophila Proteins / antagonists & inhibitors
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Embryo, Nonmammalian / metabolism
  • Eye / cytology
  • Eye / metabolism
  • Female
  • G2 Phase Cell Cycle Checkpoints
  • Gene Expression Regulation, Developmental
  • HSC70 Heat-Shock Proteins / antagonists & inhibitors
  • HSC70 Heat-Shock Proteins / genetics
  • HSC70 Heat-Shock Proteins / metabolism
  • MAP Kinase Kinase Kinases / antagonists & inhibitors
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism*
  • Mutagenesis
  • Phosphorylation
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • Drosophila Proteins
  • HSC70 Heat-Shock Proteins
  • RNA, Small Interfering
  • tlk protein, Drosophila
  • Protein Serine-Threonine Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases
  • TAK1 protein, Drosophila