Bcl-xL deamidation is a critical switch in the regulation of the response to DNA damage.
The therapeutic value of DNA-damaging antineoplastic agents is dependent upon their ability to induce tumor cell apoptosis while sparing most normal tissues. Here, we show that a component of the apoptotic response to these agents in several different types of tumor cells is the deamidation of two asparagines in the unstructured loop of Bcl-xL, and we demonstrate that deamidation of these asparagines imports susceptibility to apoptosis by disrupting the ability of Bcl-xL to block the proapoptotic activity of BH3 domain-only proteins. Conversely, Bcl-xL deamidation is actively suppressed in fibroblasts, and suppression of deamidation is an essential component of their resistance to DNA damage-induced apoptosis. Our results suggest that the regulation of Bcl-xL deamidation has a critical role in the tumor-specific activity of DNA-damaging antineoplastic agents.
Deverman
Benjamin E
BE
Division of Urology, Department of Cell Biology and Physiology, School of Medicine, Washington University, 660 South Euclid Avenue, Campus Box 8052, Saint Louis, MO 63110, USA.
Cook
Brian L
BL
Manson
Scott R
SR
Niederhoff
Robert A
RA
Langer
Ellen M
EM
Rosová
Ivana
I
Kulans
Laura A
LA
Fu
Xiaoyun
X
Weinberg
Justin S
JS
Heinecke
Jay W
JW
Roth
Kevin A
KA
Weintraub
Steven J
SJ
D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001216:Asparagine / Q000737:chemistry / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D015151:Immunoblotting; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry; D010957:Plasmids / Q000378:metabolism; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein
D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D016376:Oligonucleotides, Antisense; D010455:Peptides; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D001216:Asparagine; D002945:Cisplatin