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Interaction of CR6 (GADD45gamma ) with proliferating cell nuclear antigen impedes negative growth control
N Azam1, M Vairapandi, W Zhang
1Fels Institute for Cancer Research and Molecular Biology and the Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
Abstract:
GADD45, MyD118, and CR6 (also termed GADD45alpha, beta, and gamma) comprise a family of genes that encode for related proteins playing important roles in negative growth control, including growth suppression. Data accumulated suggest that MyD118/GADD45/CR6 serve similar but not identical functions along different apoptotic and growth suppressive pathways. It is also apparent that individual members of the MyD118/GADD45/CR6 family are differentially induced by a variety of genetic and environmental stress agents. The MyD118, CR6, and GADD45 proteins were shown to predominantly localize within the cell nucleus. Recently, we have shown that both MyD118 and GADD45 interact with proliferating cell nuclear antigen (PCNA), a protein that plays a central role in DNA replication, DNA repair, and cell cycle progression, as well as with the universal cyclin-dependent kinase inhibitor p21. In this work we show that also CR6 interacts with PCNA and p21. Moreover, it is shown that CR6 interacts with PCNA via a domain that also mediates interaction of both GADD45 and MyD118 with PCNA. Importantly, evidence has been obtained that interaction of CR6 with PCNA impedes the function of this protein in negative growth control, similar to observations reported for MyD118 and GADD45.
Insights
The GADD45 gene family, including CR6, interacts with proliferating cell nuclear antigen (PCNA) and p21. This interaction inhibits PCNA
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- The GADD45 gene family, comprising GADD45alpha, beta, and gamma (also known as MyD118 and CR6), encodes proteins involved in negative growth control and apoptosis.
- These proteins are differentially induced by various stress agents and primarily localize to the cell nucleus.
- Previous studies demonstrated interactions between MyD118/GADD45alpha and proliferating cell nuclear antigen (PCNA), a key protein in DNA replication and repair, as well as with p21, a cell cycle inhibitor.
Purpose of the Study:
- To investigate whether CR6 (GADD45gamma) also interacts with PCNA and p21.
- To identify the specific domain involved in the interaction between CR6 and PCNA.
- To determine the functional consequence of CR6-PCNA interaction on cellular growth control.
Main Methods:
- Protein-protein interaction assays were employed to demonstrate the binding of CR6 with PCNA and p21.
- Domain mapping studies were performed to pinpoint the region of CR6 responsible for PCNA interaction.
- Functional assays assessed the impact of CR6-PCNA interaction on negative growth control.
Main Results:
- CR6 (GADD45gamma) was shown to interact with both PCNA and p21.
- CR6 interacts with PCNA via the same domain that mediates the interaction of GADD45alpha and MyD118 with PCNA.
- The interaction between CR6 and PCNA was found to impede PCNA's function in negative growth control, mirroring effects observed for GADD45alpha and MyD118.
Conclusions:
- CR6, similar to GADD45alpha and MyD118, interacts with PCNA and p21.
- This interaction negatively impacts PCNA's role in growth suppression, highlighting a conserved mechanism within the GADD45 family.
- The findings contribute to understanding the multifaceted roles of GADD45 proteins in cellular stress response and growth regulation.