Figure 1.
Figure 1. The INM and lamina in normal and HGPS nuclei. (A) The INM is composed of an array of proteins responsible for maintaining nuclear function and an associated protein meshwork composed of tetrameric lamin filaments (Turgay et al., 2017). The nuclear lamina is composed of B-type lamins that are integrated into the INM and proximal but segregated lamin A/C filaments (Delbarre et al., 2006; Shimi et al., 2008, 2015; Xie et al., 2016). The structural integrity of the nucleus is also influenced by the SUN/Nesprin LINC complex that links the nucleus to the cytoskeleton (Zhang et al., 2005; Chang et al., 2015). Furthermore, integral INM proteins such as lamin B receptor, emerin, and Lap2 isoforms maintain heterochromatin at the periphery by interacting with chromatin remodeling complexes WRN, HP1/SUV39H1, PRC/NURD, and HDAC3/BAF (Makatsori et al., 2004; Somech et al., 2005; Shumaker et al., 2006; Holaska and Wilson, 2007; Montes de Oca et al., 2009; Pegoraro et al., 2009; Demmerle et al., 2012; Laugesen and Helin, 2014; Cesarini et al., 2015; Zhang et al., 2015b). Additionally, peripheral and nucleoplasmic lamin A/C may have different roles in transcription and replication via regulation of Lap2α, nuclear actin, and polymerases (Pol II; Dechat et al., 2000; Nili et al., 2001; Pekovic et al., 2007; Simon et al., 2010; de Lanerolle and Serebryannyy, 2011; Vidak et al., 2015). Through these interactions, the INM maintains proper DNA replication, DNA repair, proliferation, proinflammatory signaling via cytosolic phospholipase A2 (cPLA2), and differentiation (Dittmer and Misteli, 2011; Burke and Stewart, 2013; Enyedi et al., 2016). (B) Progerin expression and incorporation into the INM disrupts nuclear organization, causing misshapen nuclei (Goldman et al., 2004; Dahl et al., 2006; Verstraeten et al., 2008). HGPS models exhibit reduced expression of integral INM proteins such as lamin B1 and isoforms of Lap2 (Scaffidi and Misteli, 2005) and a corresponding loss of peripheral heterochromatin (Goldman et al., 2004; Scaffidi and Misteli, 2005; Shumaker et al., 2006; McCord et al., 2013). Not only is the composition of the periphery altered, but nucleoplasmic protein populations are also lost (i.e., lamin A/C and Lap2α; Dechat et al., 2000; Chojnowski et al., 2015; Vidak et al., 2015). These defects correlate with increased DNA damage, abnormal DNA damage repair, and impaired proliferation (Decker et al., 2009; Benson et al., 2010; Cao et al., 2011a; Musich and Zou, 2011; Chojnowski et al., 2015).

The INM and lamina in normal and HGPS nuclei. (A) The INM is composed of an array of proteins responsible for maintaining nuclear function and an associated protein meshwork composed of tetrameric lamin filaments (Turgay et al., 2017). The nuclear lamina is composed of B-type lamins that are integrated into the INM and proximal but segregated lamin A/C filaments (Delbarre et al., 2006; Shimi et al., 2008, 2015; Xie et al., 2016). The structural integrity of the nucleus is also influenced by the SUN/Nesprin LINC complex that links the nucleus to the cytoskeleton (Zhang et al., 2005; Chang et al., 2015). Furthermore, integral INM proteins such as lamin B receptor, emerin, and Lap2 isoforms maintain heterochromatin at the periphery by interacting with chromatin remodeling complexes WRN, HP1/SUV39H1, PRC/NURD, and HDAC3/BAF (Makatsori et al., 2004; Somech et al., 2005; Shumaker et al., 2006; Holaska and Wilson, 2007; Montes de Oca et al., 2009; Pegoraro et al., 2009; Demmerle et al., 2012; Laugesen and Helin, 2014; Cesarini et al., 2015; Zhang et al., 2015b). Additionally, peripheral and nucleoplasmic lamin A/C may have different roles in transcription and replication via regulation of Lap2α, nuclear actin, and polymerases (Pol II; Dechat et al., 2000; Nili et al., 2001; Pekovic et al., 2007; Simon et al., 2010; de Lanerolle and Serebryannyy, 2011; Vidak et al., 2015). Through these interactions, the INM maintains proper DNA replication, DNA repair, proliferation, proinflammatory signaling via cytosolic phospholipase A2 (cPLA2), and differentiation (Dittmer and Misteli, 2011; Burke and Stewart, 2013; Enyedi et al., 2016). (B) Progerin expression and incorporation into the INM disrupts nuclear organization, causing misshapen nuclei (Goldman et al., 2004; Dahl et al., 2006; Verstraeten et al., 2008). HGPS models exhibit reduced expression of integral INM proteins such as lamin B1 and isoforms of Lap2 (Scaffidi and Misteli, 2005) and a corresponding loss of peripheral heterochromatin (Goldman et al., 2004; Scaffidi and Misteli, 2005; Shumaker et al., 2006; McCord et al., 2013). Not only is the composition of the periphery altered, but nucleoplasmic protein populations are also lost (i.e., lamin A/C and Lap2α; Dechat et al., 2000; Chojnowski et al., 2015; Vidak et al., 2015). These defects correlate with increased DNA damage, abnormal DNA damage repair, and impaired proliferation (Decker et al., 2009; Benson et al., 2010; Cao et al., 2011a; Musich and Zou, 2011; Chojnowski et al., 2015).

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