New Research Shows CDK5–Cyclin B1 Regulates Mitotic Fidelity

Alexander Spektor, MD, PhD

Dipanjan Chowdhury, PhD

Study Title: CDK5–cyclin B1 regulates mitotic fidelity

Publication: Nature

Dana-Farber Cancer Institute authors: Xiao-Feng Zheng*, Aniruddha Sarkar*, Aleem Syed, Huy Nguyen, Bartlomiej Tomasik, Kaimeng Huang, Feng Li, Alan D. D’Andrea, Alexander Spektor+ and Dipanjan Chowdhury+

Summary

Cyclin Dependent Kinases (CDKs) are critical for regulating different phases of the cell cycle and CDK1 was long considered to be the only CDK responsible for mitosis. However, researchers at Dana-Farber Cancer Institute have now uncovered that CDK5, an atypical cyclin-dependent kinase essential in non-dividing neuronal cells and for central nervous system development but not believed to function during the cell cycle, plays an important role in preventing errors during normal cell division. They found that spindle microtubules that separate sister chromatids during mitosis become abnormally stable in the absence of CDK5, preventing cells from correcting chromosome attachment errors, leading to chromosome mis-segregation and formation of abnormal nuclear structures such as micronuclei. Surprisingly, they found that CDK5 accomplishes this by partnering with Cyclin B1, the same mitotic cyclin that partners with CDK1 to complete all stages of mitosis. They thus concluded that CDK5 is also a canonical cell cycle regulating CDK, essential to maintain genome stability.

Significance:

The study alters the existing paradigm that CDK1-Cyclin B1 is the only CDK-cyclin complex essential for all stages of mitosis. It also raises the possibility that other seemingly atypical CDKs may similarly have a role in regulating the progression of the cell-division cycle. Finally, while the study established the role of CDK5-Cyclin B1 during normal cell division in non-cancer cells, this complex may have an even greater role in rapidly proliferating cancer cells. CDK5 is overexpressed and hyperactivated across a broad range of cancers and this is associated with a poor prognosis. This raises the possibility that these cancers may be more dependent on CDK5 for their cell division. Thus, just like the existing therapies targeting CDKs (CDK4/6 inhibitors), CDK5 may be an important therapeutic target in cancer.

Funding:

This work was supported by grants R01 CA208244 and R01 CA264900, Gray Foundation Team Science Award, DOD Ovarian Cancer Award W81XWH-15-0564/OC140632, Tina’s Wish Foundation, Detect Me If You Can, a V Foundation Award, a Gray Foundation grant and the Claudia Adams Barr Program in Innovative Basic Cancer Research to D.C, K08 CA208008, the Burroughs Wellcome Fund Career Award for Medical Scientists, Saverin Breast Cancer Research Fund and the Claudia Adams Barr Program in Innovative Basic Cancer Research to A.S. X.-F.Z. was an American Cancer Society Fellow and is supported by the Breast and Gynecologic Cancer Innovation Award from Susan F. Smith Center for Women’s Cancers at Dana-Farber Cancer Institute. A. Syed is supported by the Claudia Adams Barr Program in Innovative Basic Cancer Research. B.T. was supported by the Polish National Agency for Academic Exchange (grant PPN/WAL/2019/1/00018) and by the Foundation for Polish Science (START Program).; A.D.D is supported by NIH grant R01 HL52725.