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Centrosomal BRCA2 is a target protein of membrane type-1 matrix metalloproteinase (MT1-MMP)

Nadila Wali1, Kana Hosokawa2, Sadiya Malik2

  • 1Department of Molecular Genetics, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Japan; Department of Obstetrics and Gynecology, Urumqi Friendship Hospital, Xinjiang, PR China.

Biochemical and Biophysical Research Communications
|January 4, 2014
PubMed

Insights

The protein BRCA2 is broken down by MT1-MMP during cell division. This cleavage regulates BRCA2

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The protein BRCA2 (Breast Cancer gene 2) is known to localize to centrosomes during specific cell cycle phases.
  • The precise mechanism controlling BRCA2's removal from centrosomes during mitosis remains unclear.
  • Centrosomes play critical roles in cell division and organization.

Purpose of the Study:

  • To elucidate the mechanism behind BRCA2's regulated removal from centrosomes during mitosis.
  • To investigate the role of specific proteases in BRCA2 centrosomal localization.
  • To understand how BRCA2 abundance at centrosomes is controlled.

Main Methods:

  • Utilized knockdown of membrane type-1 matrix metalloproteinase (MT1-MMP) to assess its effect on BRCA2.
  • Employed mass spectrometry to identify the precise cleavage site of BRCA2 by MT1-MMP.
  • Generated a point mutation (L2136D) in BRCA2 to abrogate MT1-MMP cleavage.

Main Results:

  • Demonstrated that BRCA2 is cleaved into two fragments by MT1-MMP.
  • Showed that MT1-MMP knockdown prevents BRCA2 removal from centrosomes during metaphase.
  • Identified the MT1-MMP cleavage site in human BRCA2 between Asn-2135 and Leu-2136.
  • Confirmed that the L2136D mutation abolishes MT1-MMP-mediated cleavage of BRCA2.

Conclusions:

  • MT1-MMP proteolysis is a key mechanism regulating BRCA2 abundance on centrosomes.
  • BRCA2 cleavage by MT1-MMP is essential for its proper removal during mitosis.
  • This finding provides new insights into cell cycle regulation and centrosome dynamics.
Keywords:
BRCA2CentrosomeMT1-MMP

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