Abstract
AKTIP is a shelterin-interacting protein required for replication of telomeric DNA. Here, we show that AKTIP biochemically interacts with A- and B-type lamins and affects lamin A, but not lamin C or B, expression. In interphase cells, AKTIP localizes at the nuclear rim and in discrete regions of the nucleoplasm just like lamins. Double immunostaining revealed that AKTIP partially co-localizes with lamin B1 and lamin A/C in interphase cells, and that proper AKTIP localization requires functional lamin A. In mitotic cells, AKTIP is enriched at the spindle poles and at the midbody of late telophase cells similar to lamin B1. AKTIP-depleted cells show senescence-associated markers and recapitulate several aspects of the progeroid phenotype. Collectively, our results indicate that AKTIP is a new player in lamin-related processes, including those that govern nuclear architecture, telomere homeostasis and cellular senescence.
Highlights
The nuclear lamina is a structure located between the nuclear membrane and the chromatin; it plays a scaffolding role within the nucleus and has been implicated in diverse processes including the control of nuclear architecture, DNA replication and repair, transcriptional regulation, and maintenance of telomere homeostasis [1,2,3,4,5,6]
We have recently shown that AKTIP interacts with the proliferating cell nuclear antigen (PCNA) and RPA70 components of the DNA replication machinery and with the shelterin subunits TRF1 and TRF2
Consistent with these results, we found that AKTIP is required for both general DNA replication and telomere replication [23]
Summary
The nuclear lamina is a structure located between the nuclear membrane and the chromatin; it plays a scaffolding role within the nucleus and has been implicated in diverse processes including the control of nuclear architecture, DNA replication and repair, transcriptional regulation, and maintenance of telomere homeostasis [1,2,3,4,5,6]. A- and B-type lamins are the main components of the nuclear lamina; B-type lamins are expressed in most cell types, whereas lamin A/C expression is restricted to differentiated cells [7,8]. Lamins are mainly detected at the nuclear periphery, but are found in discrete intranuclear aggregates associated with DNA replication foci or transcriptionally active areas [7]. At the end of mitosis (telophase), the lamins reassemble to form the nuclear lamina [7,9,10]. There are three lamin genes: LMNA, LMNB1 and LMNB2. Lamins A and C are alternatively spliced isoforms of the LMNA gene. Lamins B1 and B2 are the products of the LMNB1 and LMNB2 genes.
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