The highly conserved nuclear lamin Ig-fold binds to PCNA: its role in DNA replication.
This study provides insights into the role of nuclear lamins in DNA replication. Our data demonstrate that the Ig-fold motif located in the lamin C terminus binds directly to proliferating cell nuclear antigen (PCNA), the processivity factor necessary for the chain elongation phase of DNA replication. We find that the introduction of a mutation in the Ig-fold, which alters its structure and causes human muscular dystrophy, inhibits PCNA binding. Studies of nuclear assembly and DNA replication show that lamins, PCNA, and chromatin are closely associated in situ. Exposure of replicating nuclei to an excess of the lamin domain containing the Ig-fold inhibits DNA replication in a concentration-dependent fashion. This inhibitory effect is significantly diminished in nuclei exposed to the same domain bearing the Ig-fold mutation. Using the crystal structures of the lamin Ig-fold and PCNA, molecular docking simulations suggest probable interaction sites. These findings also provide insights into the mechanisms underlying the numerous disease-causing mutations located within the lamin Ig-fold.
Shumaker
Dale K
DK
Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Solimando
Liliana
L
Sengupta
Kaushik
K
Shimi
Takeshi
T
Adam
Stephen A
SA
Grunwald
Antje
A
Strelkov
Sergei V
SV
Aebi
Ueli
U
Cardoso
M Cristina
MC
Goldman
Robert D
RD
D000818:Animals; D002467:Cell Nucleus / Q000502:physiology*; D002843:Chromatin / Q000502:physiology; D004261:DNA Replication; D005260:Female; D006367:HeLa Cells; D006801:Humans; D007136:Immunoglobulins / Q000737:chemistry / Q000378:metabolism; D034904:Lamin Type A / Q000737:chemistry / Q000378:metabolism; D034921:Lamin Type B / Q000737:chemistry / Q000378:metabolism; D034882:Lamins / Q000378:metabolism*; D008297:Male; D010063:Ovum / Q000502:physiology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism*; D011485:Protein Binding; D017510:Protein Folding; D013094:Spermatozoa / Q000502:physiology; D014982:Xenopus laevis
D002843:Chromatin; D007136:Immunoglobulins; D034904:Lamin Type A; D034921:Lamin Type B; D034882:Lamins; D018809:Proliferating Cell Nuclear Antigen; C440308:lamin C